N-(aryl)-2-arylethenesulfonamides and therapeutic uses thereof

ABSTRACT

N-(Aryl)-2-arylethenesulfonamides and pharmaceutically acceptable salts and compositions thereof are useful as antiproliferative agents, including, for example, anticancer agents. They are also useful as radioprotective agents.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the priority of copending U.S.Provisional Application Serial No. 60/271,985 filed Feb. 28, 2001, theentire disclosure of which is herein incorporated by reference.

FIELD OF THE INVENTION

[0002] The invention relates to compositions and methods for thetreatment of proliferative disorders, including but not limited tocancer. The invention relates to the field of protecting normal cellsand tissues from anticipated, planned or inadvertent exposure toionizing radiation.

BACKGROUND OF THE INVENTION

[0003] α-β-Unsaturated Sulfonamides

[0004] Cancer remains a leading cause of mortality in the United Statesand in the world. To be useful, a new chemotherapeutic agent should havea wide spectrum of activity and significant therapeutic index.Styrene-ω-sulfonanilide has been prepared by reacting styrylsulfonylchloride with aniline (Bordwell et al., J. Amer. Chem. Soc. 68:139,1946). This and certain other styrene-ω-sulfonanilides have beenprepared by Knoevenagel-type synthesis as possible chemosterilantsagainst the common house fly Musca domestica L. (Oliver et al, Synthesis321-322, 1975).

[0005] U.S. Pat. No. 4,035,421 to Snyder, Jr. describes the preparationof N-(3,4-dichlorophenyl)-2-phenylethenesulfonamide and its use as anantibacterial agent.

[0006] The styrene-ω-sulfonanilides3′-hydroxy-4-nitrostyrene-β-sulfonanilide,3′-hydroxy-2-nitrostyrene-β-sulfonanilide and5′-hydroxy-2′-methyl-4-nitrostyrene-β-sulfonanilide were utilized asintermediates in the preparation of certain stilbenes by Waldau et al.Angew. Chem., Int. Ed. Engl. 11(9):826-8 (1972). Thestyrene-ω-sulfonanilides 3′-hydroxy-3-nitrostyrene-β-sulfonanilide and5′-hydroxy-2′-methyl-4-nitrostyrene-β-sulfonanilide have been utilizedin the preparation of stilbenes used as dyes (DE 2118493-Farbenfab AG).

[0007] Aswarthamma et al., Chimica Acta Turcica 24:7-10 (1996) disclosethe preparation of certain trans-(1-aryl-(2-anilinesulphonyl)ethylenes.No biological activity is set forth for the compounds. Touarti et al.,J. Soc. Alger. Chim. 6(1):39-52 (1996) disclose the preparation ofcertain α,β-unsaturated sulfonamides for inhibition of coniferyl alcoholdehydrogenase (CADH).

[0008] Except for the isolated teaching of antibacterial activity ofN-(3,4-dichlorophenyl)-2-phenylethenesulfonamide, no usefulpharmaceutical activity has been proposed for the limited numbers ofα,β-unsaturated sulfonamides known to the prior art. In particular, noanti-cell proliferation or anticancer utility has been proposed for thisclass of compounds.

[0009] New cell antiproliferative agents, and anticancer therapeutics inparticular, are needed which are useful in inhibiting proliferation ofand/or killing cancer cells. In particular, such agents are needed whichare selective in the killing of proliferating cells such as tumor cells,but not normal cells. Antineoplasitc agents are needed which areeffective against a broad range of tumor types.

[0010] Ionizing Radiation Health Risks

[0011] Ionizing radiation has an adverse effect on cells and tissues,primarily through cytotoxic effects. In humans, exposure to ionizingradiation occurs primarily through therapeutic techniques (such asanticancer radiotherapy) or through occupational and environmentalexposure.

[0012] A major source of exposure to ionizing radiation is theadministration of therapeutic radiation in the treatment of cancer orother proliferative disorders. Depending on the course of treatmentprescribed by the treating physician, multiple doses may be received bya subject over the course of several weeks to several months.

[0013] Therapeutic radiation is generally applied to a defined area ofthe subject's body which contains abnormal proliferative tissue, inorder to maximize the dose absorbed by the abnormal tissue and minimizethe dose absorbed by the nearby normal tissue. However, it is difficult(if not impossible) to selectively administer therapeutic ionizingradiation to the abnormal tissue. Thus, normal tissue proximate to theabnormal tissue is also exposed to potentially damaging doses ofionizing radiation throughout the course of treatment. There are alsosome treatments that require exposure of the subject's entire body tothe radiation, in a procedure called “total body irradiation”, or “TBI.”The efficacy of radiotherapeutic techniques in destroying abnormalproliferative cells is therefore balanced by associated cytotoxiceffects on nearby normal cells. Because of this, radiotherapy techniqueshave an inherently narrow therapeutic index which results in theinadequate treatment of most tumors. Even the best radiotherapeutictechniques may result in incomplete tumor reduction, tumor recurrence,increasing tumor burden, and induction of radiation resistant tumors.

[0014] Numerous methods have been designed to reduce normal tissuedamage while still delivering effective therapeutic doses of ionizingradiation. These techniques include brachytherapy, fractionated andhyperfractionated dosing, complicated dose scheduling and deliverysystems, and high voltage therapy with a linear accelerator. However,such techniques only attempt to strike a balance between the therapeuticand undesirable effects of the radiation, and full efficacy has not beenachieved.

[0015] For example, one treatment for subjects with metastatic tumorsinvolves harvesting their hematopoietic stem cells and then treating thesubject with high doses of ionizing radiation. This treatment isdesigned to destroy the subject's tumor cells, but has the side effectof also destroying their normal hematopoietic cells. Thus, a portion ofthe subject's bone marrow (containing the hematopoietic stem cells), isremoved prior to radiation therapy. Once the subject has been treated,the autologous hematopoietic stem cells are returned to their body.

[0016] However, if tumor cells have metastasized away from the tumor'sprimary site, there is a high probability that some tumor cells willcontaminate the harvested hematopoietic cell population. The harvestedhematopoietic cell population may also contain neoplastic cells if thesubject suffers from a cancers of the bone marrow such as the variousFrench-American-British (FAB) subtypes of acute myelogenous leukemias(AML), chronic myeloid leukemia (CML), or acute lymphocytic leukemia(ALL). Thus, the metastasized tumor cells or resident neoplastic cellsmust be removed or killed prior to reintroducing the stem cells to thesubject. If any living tumorigenic or neoplastic cells are reintroducedinto the subject, they can lead to a relapse.

[0017] Prior art methods of removing tumorigenic or neoplastic cellsfrom harvested bone marrow are based on a whole-population tumor cellseparation or killing strategy, which typically does not kill or removeall of the contaminating malignant cells. Such methods includeleukopheresis of mobilized peripheral blood cells, immunoaffinity-basedselection or killing of tumor cells, or the use of cytotoxic orphotosensitizing agents to selectively kill tumor cells. In the bestcase, the malignant cell burden may still be at 1 to 10 tumor cells forevery 100,000 cells present in the initial harvest (Lazarus et al. J. ofHematotherapy, 2(4):457-66, 1993).

[0018] Thus, there is needed a purging method designed to selectivelydestroy the malignant cells present in the bone marrow, while preservingthe normal hematopoietic stem cells needed for hematopoieticreconstitution in the transplantation subject.

[0019] Exposure to ionizing radiation can also occur in the occupationalsetting. Occupational doses of ionizing radiation may be received bypersons whose job involves exposure (or potential exposure) toradiation, for example in the nuclear power and nuclear weaponsindustries. Military personnel stationed on vessels powered by nuclearreactors, or soldiers required to operate in areas contaminated byradioactive fallout, risk similar exposure to ionizing radiation.Occupational exposure may also occur in rescue and emergency personnelcalled in to deal with catastrophic events involving a nuclear reactoror radioactive material. Other sources of occupational exposure may befrom machine parts, plastics, and solvents left over from themanufacture of radioactive medical products, smoke alarms, emergencysigns, and other consumer goods. Occupational exposure may also occur inpersons who serve on nuclear powered vessels, particularly those whotend the nuclear reactors, in military personnel operating in areascontaminated by nuclear weapons fallout, and in emergency personnel whodeal with nuclear accidents. Environmental exposure to ionizingradiation may also result from nuclear weapons detonations (eitherexperimental or during wartime), discharges of actinides from nuclearwaste storage and processing and reprocessing of nuclear fuel, and fromnaturally occurring radioactive materials such as radon gas or uranium.There is also increasing concern that the use of ordnance containingdepleted uranium results in low-level radioactive contamination ofcombat areas.

[0020] Radiation exposure from any source can be classified as acute (asingle large exposure) or chronic (a series of small low-level, orcontinuous low-level exposures spread over time). Radiation sicknessgenerally results from an acute exposure of a sufficient dose, andpresents with a characteristic set of symptoms that appear in an orderlyfashion, including hair loss, weakness, vomiting, diarrhea, skin bumsand bleeding from the gastrointestinal tract and mucous membranes.Genetic defects, sterility and cancers (particularly bone marrow cancer)often develop over time. Chronic exposure is usually associated withdelayed medical problems such as cancer and premature aging. An acute atotal body exposure of 125,000 millirem may cause radiation sickness.Localized doses such as are used in radiotherapy may not cause radiationsickness, but may result in the damage or death of exposed normal cells.

[0021] For example, an acute total body radiation dose of 100,000-125,000 millirem (equivalent to 1 Gy) received in less than one weekwould result in observable physiologic effects such as skin bums orrashes, mucosal and GI bleeding, nausea, diarrhea and/or excessivefatigue. Longer term cytotoxic and genetic effects such as hematopoieticand immunocompetent cell destruction, hair loss (alopecia),gastrointestinal, and oral mucosal sloughing, venoocclusive disease ofthe liver and chronic vascular hyperplasia of cerebral vessels,cataracts, pneumonites, skin changes, and an increased incidence ofcancer may also manifest over time. Acute doses of less than 10,000millirem (equivalent to 0.1 Gy) typically will not result in immediatelyobservable biologic or physiologic effects, although long term cytotoxicor genetic effects may occur.

[0022] A sufficiently large acute dose of ionizing radiation, forexample 500,000 to over 1 million millirem (equivalent to 5-10 Gy), maykill a subject immediately. Doses in the hundreds of thousands ofmillirems may kill within 7 to 21 days from a condition called “acuteradiation poisoning.” Reportedly, some of the Chernobyl firefightersdied of acute radiation poisoning, having received acute doses in therange of 200,000-600,000 millirem (equivalent to 2-6 Gy). Acute dosesbelow approximately 200,000 millirem do not result in death, but theexposed subject will likely suffer long-term cytotoxic or geneticeffects as discussed above.

[0023] Acute occupational exposures usually occur in nuclear power plantworkers exposed to accidental releases of radiation, or in fire andrescue personnel who respond to catastrophic events involving nuclearreactors or other sources of radioactive material. Suggested limits foracute occupational exposures in emergency situations were developed bythe Brookhaven National Laboratories, and are given in Table 1. TABLE 1Acute Occupational Exposure Limits for Emergency Operations Whole BodyConditions for Dose Limit Activity Required Conditions for Exposure  10,000 millirem* Protect property Voluntary, when lower dose notpractical   25,000 millirem Lifesaving Operation; Voluntary, when lowerProtect General Public dose not practical >25,000 millirem Lifesavingoperation; Voluntary, when lower Protect large population dose notpractical, and the risk has been clearly explained

[0024] A chronic dose is a low level (i.e., 100-5000 millirem)incremental or continuous radiation dose received over time. Examples ofchronic doses include a whole body dose of ˜5000 millirem per year,which is the dose typically received by an adult working at a nuclearpower plant. By contrast, the Atomic Energy Commission recommends thatmembers of the general public should not receive more than 100 milliremper year. Chronic doses may cause long-term cytotoxic and geneticeffects, for example manifesting as an increased risk of aradiation-induced cancer developing later in life. Recommended limitsfor chronic exposure to ionizing radiation are given in Table 2. TABLE 2Annual Chronic Occupational Radiation Exposure Limits Organ or SubjectAnnual Occupational Dose in millirem Whole Body   5000 Lens of the Eye15,000 Hands and wrists 50,000 Any individual organ 50,000 Pregnantworker   500/9 months Minor (16-18) receiving training   100

[0025] By way of comparison, Table 3 sets forth the radiation doses fromcommon sources. TABLE 3 Radiation Dosages From Common Sources SourcesDose In Millirem Television    <1/yr Gamma Rays, Jet Cross Country     1Mountain Vacation - 2 week     3 Atomic Test Fallout     5 U.S. Water,Food & Air (Average)    30/yr Wood    50/yr Concrete    50/yr Brick   75/yr Chest X-Ray    100 Cosmic Radiation (Sea Level)    40/yr (add 1millirem/ 100 ft elev.) Natural Background San Francisco    120/yrNatural Background Denver    50/yr Atomic Energy Commission Limit ForWorkers   5000/yr Complete Dental X-Ray   5000 Natural Background atPocos de Caldras, Brazil   7000/yr Whole Body Diagnostic X-Ray 100,000Cancer Therapy 500,000 (localized) Radiation Sickness-Nagasaki 125,000(single doses) LD₅₀ Nagasaki & Hiroshima 400,000-500,000 (single dose)

[0026] Chronic doses of greater than 5000 millirem per year (0.05 Gy peryear) may result in long-term cytotoxic or genetic effects similar tothose described for persons receiving acute doses. Some adversecytotoxic or genetic effects may also occur at chronic doses ofsignificantly less than 5000 millirem per year. For radiation protectionpurposes, it is assumed that any dose above zero can increase the riskof radiation-induced cancer (i.e., that there is no threshold).Epidemiologic studies have found that the estimated lifetime risk ofdying from cancer is greater by about 0.04% per rem of radiation dose tothe whole body.

[0027] While anti-radiation suits or other protective gear may beeffective at reducing radiation exposure, such gear is expensive,unwieldy, and generally not available to public. Moreover,radioprotective gear will not protect normal tissue adjacent a tumorfrom stray radiation exposure during radiotherapy. What is needed,therefore, is a practical way to protect subjects who are scheduled toincur, or are at risk for incurring, exposure to ionizing radiation. Inthe context of therapeutic irradiation, it is desirable to enhanceprotection of normal cells while causing tumor cells to remainvulnerable to the detrimental effects of the radiation. Furthermore, itis desirable to provide systemic protection from anticipated orinadvertent total body irradiation, such as may occur with occupationalor environmental exposures, or with certain therapeutic techniques.

[0028] Pharmaceutical radioprotectants offer a cost-efficient, effectiveand easily available alternative to radioprotective gear. However,previous attempts at radioprotection of normal cells with pharmaceuticalcompositions have not been entirely successful. For example, cytokinesdirected at mobilizing the peripheral blood progenitor cells confer amyeloprotective effect when given prior to radiation (Neta et al.,Semin. Radiat. Oncol. 6:306-320, 1996), but do not confer systemicprotection. Other chemical radioprotectors administered alone or incombination with biologic response modifiers have shown minor protectiveeffects in mice, but application of these compounds to large mammals wasless successful, and it was questioned whether chemical radioprotectionwas of any value (Maisin, J. R., Bacq and Alexander Award Lecture.“Chemical radioprotection: past, present, and future prospects”, Int J.Radiat Biol. 73:443-50, 1998). Pharmaceutical radiation sensitizers,which are known to preferentially enhance the effects of radiation incancerous tissues, are clearly unsuited for the general systemicprotection of normal tissues from exposure to ionizing radiation.

[0029] What is needed are therapeutic agents to protect subjects whohave incurred, or are at risk for incurring exposure to ionizingradiation. In the context of therapeutic irradiation, it is desirable toenhance protection of normal cells while causing tumor cells to remainvulnerable to the detrimental effects of the radiation. Furthermore, itis desirable to provide systemic protection from anticipated orinadvertent total body irradiation, such as may occur with occupationalor environmental exposures, or with certain therapeutic techniques.

SUMMARY OF THE INVENTION

[0030] It is an object of the invention to provide compounds,compositions and therapeutic methods. The biologically active compoundsare in the form of N-(aryl)-2-arylethenesulfonamides, andpharmaceutically acceptable salts thereof.

[0031] It is an object of the invention to provide compounds,compositions and methods for the treatment of cancer and otherproliferative diseases.

[0032] It is an object of the invention to provide compounds which areselective in killing tumor cells but not normal cells.

[0033] It is an object of the invention to provide compounds,compositions and methods for inducing neoplastic cells to selectivelyundergo apoptosis.

[0034] It is an object of the invention to provide compounds,compositions and methods for protecting normal cells and tissues fromthe cytotoxic and genetic effects of exposure to ionizing radiation, insubjects who have incurred or are at risk for incurring exposure toionizing radiation. The exposure to ionizing radiation may occur incontrolled doses during the treatment of cancer and other proliferativedisorders, or may occur in uncontrolled doses beyond the norm acceptedfor the population at large during high risk activities or environmentalexposures.

[0035] In another aspect, a method of treating a subject for cancer orother proliferative disorders is provided, comprising administering tothe subject an effective amount of at least one radioprotectantN-(aryl)-2-arylethenesulfonamide compound prior to administering aneffective amount of ionizing radiation, wherein the radioprotectiveN-(aryl)-2-arylethenesulfonamide compound induces a temporaryradioresistant phenotype in the subject's normal tissue.

[0036] In a further aspect, the invention provides a method of safelyincreasing the dosage of therapeutic ionizing radiation used in thetreatment of cancer or other proliferative disorders, comprisingadministering an effective amount of at least one radioprotectiveN-(aryl)-2-arylethenesulfonamide compound prior to administration of thetherapeutic ionizing radiation, which radioprotective compound induces atemporary radioresistant phenotype in the subject's normal tissue.

[0037] In yet a further aspect, the invention provides a method fortreating individuals who have incurred or are at risk for incurringremediable radiation damage from exposure to ionizing radiation. In oneembodiment, an effective amount of at least one radioprotectiveN-(aryl)-2-arylethenesulfonamide compound is administered to the subjectbefore the subject incurs remediable radiation damage from exposure toionizing radiation. In another embodiment, an effective amount of atleast one radioprotective N-(aryl)-2-arylethenesulfonamide compound isadministered to the subject after the subject incurs remediableradiation damage from exposure to ionizing radiation.

[0038] In yet another embodiment, the invention provides a method forpurging bone marrow of neoplastic cells (such as leukemic cells) ortumor cells which have metastasized into the bone marrow, comprisingharvesting bone marrow cells from an individual afflicted with aproliferative disorder, treating the harvested bone marrow cells with aneffective amount of at least one N-(aryl)-2-arylethenesulfonamidecompound, and subjecting the treated bone marrow cells to an effectiveamount of ionizing radiation. The harvested cells are then returned tothe body of the afflicted individual.

[0039] In another aspect, the invention is directed to novel compoundsof formula I:

[0040] wherein:

[0041] Q₁, and Q₂ are independently selected from the group consistingof substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl;

[0042] R is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,(C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl(C₁-C₃)alkyl,substituted heteroaryl(C₁-C₃)alkyl and unsubstitutedheteroaryl(C₁-C₃)alkyl;

[0043] wherein the substituents for the substituted aryl and substitutedheteroaryl groups comprising Q₁ are independently selected from thegroup consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, cyano,carboxy, carboxy(C1-C3)alkoxy, hydroxy, (C2-C6)hydroxyalkyl,phosphonato, amino, (C1-C6)acylamino, sulfamyl, acetoxy,di(C1-C6)alkylamino(C2-C6 alkoxy), trifluoromethyl and

[0044] wherein the substituents for the substituted aryl and substitutedheteroaryl groups comprising Q₁, are independently selected from thegroup consisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano,carboxy, carboxy(C₁-C₃)alkoxy, hydroxy, (C₂-C₆)hydroxyalkyl,phosphonato, amino, (C₁-C₆)acylamino, sulfamyl, acetoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy, trifluoromethyl and

[0045] wherein:

[0046] X is oxygen or sulfur,

[0047] R⁵ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted phenyl and unsubstitutedphenyl, and

[0048] R⁶ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted aryl, unsubstituted aryl,substituted heteroaryl, unsubstituted heteroaryl, substitutedaryl-(C₁-C₃)alkyl, unsubstituted aryl-(C₁-C₃)alkyl and(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl; and

[0049] wherein the substituents for the substituted aryl and substitutedheteroaryl groups comprising Q₂, and the substituents for thesubstituted aryl and substituted heteroaryl groups comprising orincluded within R, R⁵ and R⁶, are independently selected from the groupconsisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano,carboxy, carboxy(C₁-C₃)alkoxy, hydroxy, (C₂-C₆)hydroxyalkyl,phosphonato, amino, (C₁-C₆)acylamino, sulfamyl, acetoxy,di(C₁-C₆)alkylamino(C₂-C₆)alkoxy and trifluoromethyl;

[0050] provided, that when R is hydrogen:

[0051] (a) when Q₁ is unsubstituted phenyl, Q₂ is other thandimethoxyphenyl, 2-methylphenyl, 2-chlorophenyl, 4-chlorophenyl,4-N,N-dimethylaminophenyl, 4-methylphenyl, 4-methoxyphenyl,4-nitrophenyl, 3-methoxy-4-hydroxyphenyl, unsubstituted phenyl,unsubstituted pyrenyl, unsubstituted benzodioxolyl, unsubstituted1-naphthyl and unsubstituted 2-thienyl; in a sub-embodiment, when Q₁ isunsubstituted phenyl, Q₂ is other than dialkoxyphenyl, 2-alkylphenyl,2-halophenyl, 4-halophenyl, 4-N,N-dialkylaminophenyl, 4-alkylphenyl,4-alkoxyphenyl, 4-nitrophenyl, 3-alkoxy-4-hydroxyphenyl, unsubstitutedphenyl, unsubstituted pyrenyl, unsubstituted benzodioxolyl,unsubstituted 1-naphthyl and unsubstituted 2-thienyl;

[0052] (b) when Q₁ is 2,4-dinitrophenyl, Q₂ is other than4-methylphenyl, 4-methoxyphenyl, 4-nitrophenyl, 4-bromophenyl,3,4-dichlorophenyl, unsubstituted phenyl or unsubstituted 1-naphthyl; ina sub-embodiment, when Q₁ is 2,4-dinitrophenyl, Q₂ is other than4-alkylphenyl, 4-alkoxyphenyl, 4-nitrophenyl, 4-halophenyl,3,4-dihalophenyl, unsubstituted phenyl or unsubstituted 1-naphthyl;

[0053] (c) when Q₁ is 3-hydroxyphenyl, Q₂ is other than 2-nitrophenyl,or 3-nitrophenyl; in a sub-embodiment, when Q₁ is 3-hydroxyphenyl, Q₂ isother than nitrophenyl;

[0054] (d) when Q₁ is 2-methyl-5-hydroxyphenyl, Q₂ is other than4-nitrophenyl; in a sub-embodiment, when Q₁ is 2-methyl-5-hydroxyphenyl,Q₂ is other than 4-nitrophenyl;

[0055] (e) when Q₁ is unsubstituted 2-pyridyl, Q₂ is other than3-methoxy-4-hydroxyphenyl; in a sub-embodiment, when Q₁ is unsubstituted2-pyridyl, Q₂ is other than 3-methoxy-4-hydroxyphenyl; and

[0056] (f) when Q₂ is unsubstituted phenyl, Q₁ is other than2-hydroxyphenyl, 2-aminophenyl, 3,4-dichlorophenyl or unsubstituted2-pyridyl; in a sub-embodiment, when Q₂ is unsubstituted phenyl, Q₁ isother than 2-hydroxyphenyl, 2-aminophenyl, 3,4-dihalophenyl orunsubstituted 2-pyridyl; or a pharmaceutically acceptable salt thereof.

[0057] In a further sub-embodiment, novel compounds of formula I areprovided wherein Q₁ and Q₂ are independently selected from the groupconsisting of substituted aryl and substituted heteroaryl; R is definedas above; the substituents for the substituted aryl and substitutedheteroaryl groups comprising Q₁ are defined as above; the substituentsfor the substituted aryl and substituted heteroaryl groups comprisingQ_(2,) and the substituents for the substituted aryl and substitutedheteroaryl groups comprising or included within R, R⁵ and R⁶, aredefined as above,

[0058] provided, when R is hydrogen:

[0059] (i) Q₁ may not be dinitrophenyl;

[0060] (ii) Q₂ may not be dinitrophenyl; and

[0061] (iii) when Q₂ is mononitrophenyl:

[0062] Q₁ is other than substituted phenyl, or

[0063] Q₁ is substituted phenyl wherein at least the 4-position issubstituted, and the substituent is other than hydroxy;

[0064] or a pharmaceutically acceptable salt thereof.

[0065] According to another embodiment, the invention is directed to aprocess for preparing a novel compound as defined above, the processcomprising reacting a compound of the formula B:

[0066] with a compound of the formula C

[0067] in a nonprotic solvent in the presence of a base to form acompound of the formula:

[0068] wherein R, Q₁ and Q₂ are defined as above. Compound B may beprepared by reacting a compound of the formula A, Q₂—CH═CH₂, withsulfonyl chloride in the presence of a nonprotic solvent.

[0069] According to another embodiment, the invention is directed to analternative process for preparing a novel compound as defined above,said process comprising reacting a compound of the formula G

[0070] with a compound of the formula H

[0071] in the presence of a basic catalyst to form a compound of theformula:

[0072] wherein R, Q₁ and Q₂ are defined as above.

[0073] Compounds of formula G may be prepared by reacting a compound ofthe formula E, ClSO₂—CH₂—C(O)OR′, with a compound of formula C (asdefined above) in a nonprotic solvent in the presence of a base to forma compound of the formula F,

[0074] and then treating the formula F compound with a base capable ofhydrolyzing the ester function thereof to an acid to form compound G;wherein R and Q₁ are defined as above, and R′ is methyl or ethyl.

[0075] According to another embodiment of the invention, pharmaceuticalcompositions are provided comprising a pharmaceutically acceptablecarrier and a compound according to formula I wherein

[0076] Q₁ and Q₂ are independently selected from the group consisting ofsubstituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl; and R is defined as above;

[0077] wherein the substituents for the substituted aryl and substitutedheteroaryl groups comprising Q₁ are independently selected from thegroup consisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano,carboxy, carboxy(C₁-C₃)alkoxy, hydroxy, (C₂-C₆)hydroxyalkyl,phosphonato, amino, (C₁-C₆)acylamino, sulfamyl, acetoxy,di(C₁-C₆)alkylamino(C₂-C₆)alkoxy, trifluoromethyl and

[0078] wherein:

[0079] X is oxygen or sulfur,

[0080] R⁵ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted phenyl and unsubstitutedphenyl, and

[0081] R⁶ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted aryl, unsubstituted aryl,substituted heteroaryl, unsubstituted heteroaryl, substitutedaryl-(C₁-C₃)alkyl, unsubstituted aryl-(C₁-C₃)alkyl and(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl; and

[0082] wherein the substituents for the substituted aryl and substitutedheteroaryl groups comprising Q₂, and the substituents for thesubstituted aryl and substituted heteroaryl groups comprising orincluded within R, R⁵ and R⁶, are independently selected from the groupconsisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano,carboxy, carboxy(C₁-C₃)alkoxy, hydroxy, (C₂-C₆)hydroxyalkyl,phosphonato, amino, (C₁-C₆)acylamino, sulfamyl, acetoxy,di(C₁-C₆)alkylamino(C₂-C₆)alkoxy and trifluoromethyl;

[0083] provided, when R is hydrogen and Q₂ is unsubstituted phenyl, thenQ₁ must be other than 3,4-dichlorophenyl, more particularly other than3,4-dihalophenyl, even more particularly other than dihalophenyl;

[0084] or a pharmaceutically acceptable salt thereof.

[0085] According to another embodiment of the invention, a method oftreating an individual for a proliferative disorder comprisesadministering to said individual an effective amount of at least oneN-(aryl)-2-arylethenesulfonamide compound.

[0086] According to another embodiment of the invention, a method ofinducing apoptosis of tumor cells in an individual afflicted with canceris provided, comprising administering to said individual an effectiveamount of at least one N-(aryl)-2-arylethenesulfonamide compound.

[0087] According to another embodiment of the invention, a method ofreducing or eliminating the effects of ionizing radiation on normalcells in a subject who has incurred or is at risk for incurring exposureto ionizing radiation is provided. An effective amount of at least oneN-(aryl)-2-arylethenesulfonamide compound is administered to the subjectprior to or after exposure to ionizing radiation.

[0088] A method of safely increasing the dosage of therapeutic ionizingradiation used in the treatment of cancer or other proliferativedisorders is also provided. The method comprises administering aneffective amount of at least one radioprotectiveN-(aryl)-2-arylethenesulfonamide compound prior to administration of thetherapeutic ionizing radiation, which radioprotective compound induces atemporary radioresistant phenotype in the normal tissue of the subject.

[0089] A method for treating a subject who has incurred or is at riskfor incurring remediable radiation damage from exposure to ionizingradiation comprises administering an effective amount of at least oneradioprotective N-(aryl)-2-arylethenesulfonamide compound prior to orafter incurring remedial radiation damage from exposure to ionizingradiation.

[0090] For all of the aforementioned therapeutic methods, theadministered compound is a compound according to formula I wherein:

[0091] Q₁ and Q₂ are independently selected from the group consisting ofsubstituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl;

[0092] R is defined as above;

[0093] wherein the substituents for the substituted aryl and substitutedheteroaryl groups comprising Q₁ are independently selected from thegroup consisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano,carboxy, carboxy(C₁-C₃)alkoxy, hydroxy, (C₂-C₆)hydroxyalkyl,phosphonato, amino, (C₁-C₆)acylamino, sulfamyl, acetoxy,di(C₁-C₆)alkylamino(C₂-C₆)alkoxy, trifluoromethyl and

[0094] wherein:

[0095] X is oxygen or sulfur,

[0096] R⁵ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted phenyl and unsubstitutedphenyl, and

[0097] R⁶ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted aryl, unsubstituted aryl,substituted heteroaryl, unsubstituted heteroaryl, substitutedaryl-(C₁-C₃)alkyl, unsubstituted aryl-(C₁-C₃)alkyl and(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl; and

[0098] wherein the substituents for the substituted aryl and substitutedheteroaryl groups comprising Q₂, and the substituents for thesubstituted aryl and substituted heteroaryl groups comprising orincluded within R, R⁵ and R⁶, are independently selected from the groupconsisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano,carboxy, carboxy(C₁-C₃)alkoxy, hydroxy, (C₂-C₆)hydroxyalkyl,phosphonato, amino, (C₁-C₆)acylamino, sulfamyl, acetoxy,di(C₁-C₆)alkylamino(C₂-C₆)alkoxy and trifluoromethyl;

[0099] or a pharmaceutically acceptable salt thereof.

[0100] The term “acyl” means a radical of the general formula —C(═O)—R,wherein —R is hydrogen, hydrocarbyl, amino or alkoxy. Examples includefor example, acetyl (—C(═O)CH₃), propionyl (—C(═O)CH₂CH₃), benzoyl(—C(═O)C₆H₅). Phenylacetyl (—C(═O)CH₂C₆H₅), carboethoxy (—CO₂Et), anddimethylcarbamoyl (—C(═O)N(CH₃)₂).

[0101] The term “aromatic” refers to a carbocycle or heterocycle havingone or more polyunsaturated rings having aromatic character (4n+2)delocalized π(pi) electrons).

[0102] The term “(C₂-C₆)acylamino” means a radical containing a two tosix carbon straight or branched chain acyl group attached to a nitrogenatom via the acyl carbonyl carbon. Examples include —NHC(O)CH₂CH₂CH₃ and—NHC(O)CH₂CH₂ CH₂CH₂CH₃.

[0103] The term “alkyl”, by itself or as part of another substituentmeans, unless otherwise stated, a straight or branched chain hydrocarbonradical, including di- and multi-radicals, having the number of carbonatoms designated (i.e. (C₁-C₆) means one to six carbons) and includesstraight or branched chain groups. Most preferred is (C₁-C₃)alkyl, ethylor methyl.

[0104] The term “alkoxy” employed alone or in combination with otherterms means, unless otherwise stated, an alkyl group having thedesignated number of carbon atoms, as defined above, connected to therest of the molecule via an oxygen atom, such as, for example, methoxy,ethoxy, 1-propoxy, 2-propoxy and the higher homologs and isomers.Preferred are (C₁-C₃)alkoxy, ethoxy or methoxy.

[0105] The term “alkylenyl” by itself or as part of another substituentmeans a divalent radical derived from a straight or branched chainalkane having the indicated number of carbon atoms, as exemplified bythe four-carbon radical —CH₂ CH₂CH₂CH₂—.

[0106] The term “alkenyl” employed alone or in combination with otherterms, means, unless otherwise stated, a stable straight chain orbranched monounsaturated or diunsaturated hydrocarbon group having thestated number of carbon atoms. Examples include vinyl, propenyl (allyl),crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, andthe higher homologs and isomers. A divalent radical derived from analkene is exemplified by —CH═CH—CH₂—.

[0107] The term —carboxy(C₁-C₃)alkoxy” means a radical in which thecarboxy group —COOH is attached to a carbon of a straight or branchedchain alkoxy group containing one to three carbon atoms. The radicalthus contains up to four carbon atoms. Examples includeHOC(O)CH₂CH₂CH₂O— and HOC(O)CH₂CH₂O—.

[0108] The term “heteroalkyl” by itself or in combination with anotherterm means, unless otherwise stated, a stable straight or branched chainradical consisting of the stated number of carbon atoms and one or twoheteroatoms selected from the group consisting of O, N, and S, andwherein the nitrogen and sulfur atoms may be optionally oxidized and thenitrogen heteroatom may be optionally quatemized. The heteroatom(s) maybe placed at any position of the heteroalkyl group, including betweenthe rest of the heteroalkyl group and the fragment to which it isattached, as well as attached to the most distal carbon atom in theheteroalkyl group. Examples include: —O—CH₂—CH₂—CH₃, —CH₂—CH₂CH₂—OH,—CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, and —CH₂CH₂—S(O)—CH₃. Up to twoheteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃.

[0109] The term “heteroalkenyl” by itself or in combination with anotherterm means, unless otherwise stated, a stable straight or branched chainmonounsaturated or diunsaturated hydrocarbon radical consisting of thestated number of carbon atoms and one or two heteroatoms selected fromthe group consisting of O, N, and S, and wherein the nitrogen and sulfuratoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quatemized. Up to two heteroatoms may be placedconsecutively. Examples include —CH═CH—O—CH₃, —CH═CH—CH₂—OH,—CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, and —CH₂—CH═CH—CH₂—SH.

[0110] The term “hydroxyalkyl” means an alkyl radical wherein one ormore of the carbon atoms is substituted with hydroxy. Examples include—CH₂CH(OH)CH₃ and —CH₂CH₂OH. The terms “halo” or “halogen” by themselvesor as part of another substituent mean, unless otherwise stated, afluorine, chlorine, bromine, or iodine atom.

[0111] The term “(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl” means a group ofthe formula CH₃(CH₂)_(p)OC(O)(CH₂)_(q)— wherein p is an integer fromzero to five and q is an integer from one to six.

[0112] The term “di(C₁-C₆)alkylamino(C₂-C₆)alkoxy” means(alkyl)₂N(CH₂)_(n)O— wherein the two alkyl chains connected to thenitrogen atom independently contain from one to six carbon atoms,preferably from one to three carbon atoms, and n is an integer from 2 to6. Preferably, n is 2 or 3. Most preferably, n is 2, and the alkylgroups are methyl, that is, the group is the dimethylaminoethoxy group,(CH₃)₂NCH₂CH₂O—.

[0113] The term “phosphonato” means the group —PO(OH)₂.

[0114] The term “sulfamyl” means the group —SO₂NH₂.

[0115] The term “aryl” employed alone or in combination with otherterms, means, unless otherwise stated, a carbocyclic aromatic systemcontaining one or more rings (typically one, two or three rings) whereinsuch rings may be attached together in a pendent manner or may be fused.Examples include phenyl; anthracyl; and naphthyl, particularlyl-naphthyland 2-naphthyl.

[0116] The term “aryl-(C₁-C₃)alkyl” means a radical wherein a one tothree carbon alkylene chain is attached to an aryl group, e.g.,—CH₂CH₂-phenyl. Similarly, the term “heteroaryl-(C₁-C₃)alkyl” means aradical wherein a one to three carbon alkylene chain is attached to aheteroaryl group, e.g., —CH₂CH₂-pyridyl. The term “substitutedaryl-(C₁-C₃)alkyl” means an aryl-(C₁-C₃)alky radical in which the arylgroup is substituted. The term “substituted heteroaryl-(C₁C₃)alkyl”means a heteroaryl-(C₁-C₃)alky radical in which the heteroaryl group issubstituted.

[0117] The term “heteroaryl” by itself or as part of another substituentmeans, unless otherwise stated, an unsubstituted or substituted, stable,mono- or multicyclic heterocyclic aromatic ring system which consists ofcarbon atoms and from one to four heteroatoms selected from the groupconsisting of N, O, and S, and wherein the nitrogen and sulfurheteroatoms may be optionally oxidized, and the nitrogen atom may beoptionally quaternized. The heterocyclic system may be attached, unlessotherwise stated, at any heteroatom or carbon atom which affords astable structure.

[0118] Examples of such heteroaryls include benzimidazolyl, particularly2-benzimidazolyl; benzofuryl, particularly 3-, 4-, 5-, 6- and7-benzofuryl; 2-benzothiazolyl and 5-benzothiazolyl; benzothienyl,particularly 3-, 4-, 5-, 6-, and 7-benzothienyl; 4-(2-benzyloxazolyl);furyl, particularly 2- and 3-furyl; isoquinolyl, particularly 1- and5-isoquinolyl; isoxazolyl, particularly 3-, 4- and 5-isoxazolyl;imidazolyl, particularly 2-, -4 and 5-imidazolyl; indolyl, particularly3-, 4-, 5-, 6- and 7-indolyl; oxazolyl, particularly 2-, 4- and5-oxazolyl; purinyl; pyrrolyl, particularly 2-pyrrolyl, 3-pyrrolyl;pyrazolyl, particularly 3- and 5-pyrazolyl; pyrazinyl, particularly2-pyrazinyl; pyridazinyl, particularly 3- and 4-pyridazinyl; pyridyl,particularly 2-, 3- and 4-pyridyl; pyrimidinyl, particularly 2- and4-pyrimidyl; quinoxalinyl, particularly 2- and 5-quinoxalinyl;quinolinyl, particularly 2- and 3-quinolinyl; 5-tetrazolyl; thiazolyl;particularly 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; thienyl,particularly 2- and 3-thienyl; and 3-(1,2,4-triazolyl). Theaforementioned listing of heteroaryl moieties is intended to berepresentative, not limiting. In another embodiment of the invention, Q₁is independently selected from the group consisting of substituted andunsubstituted aryl, and substituted and unsubstituted heteroaryl,provided that Q₁, is not 2-thiazolyl. In a further embodiment of theinvention, Q₁ is independently selected from the group consisting ofsubstituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl, provided that Q₁ is not 2-thiazolyl, 4-thiazolyl or5-thiazolyl.

[0119] The term “substituted” means that an atom or group of atoms hasreplaced hydrogen as the substituent attached to another group. For aryland heteroaryl groups, the “substituted” is meant any level ofsubstitution, namely mono-, di-, tri-, tetra-, or penta-substitution.The substituents are independently selected.

[0120] For purposes of this disclosure, the term aryl in the expression“N-(aryl)-2-arylethenesulfonamide” is deemed to include both “aryl” and“heteroaryl” radicals, either substituted or unsubstituted, unlessotherwise indicated.

[0121] The term “subject” or “individual” includes human beings andnon-human animals. With respect to the disclosed radioprotectivemethods, these terms further refer to an organism which is scheduled toincur, is at risk for incurring, or has incurred, exposure to ionizingradiation.

[0122] As used herein, “ionizing radiation” is radiation of sufficientenergy that, when absorbed by cells and tissues, induces formation ofreactive oxygen species and DNA damage. This type of radiation includesX-rays, gamma rays, and particle bombardment (e.g., neutron beam,electron beam, protons, mesons and others), and is used for medicaltesting and treatment, scientific purposes, industrial testing,manufacturing and sterilization, weapons and weapons development, andmany other uses. Radiation is typically measured in units of absorbeddose, such as the rad or gray (Gy), or in units of dose equivalence,such as the rem or sievert (Sv). The relationship between these units isgiven below: rad and gray (Gy) rem and sievert (Sv) 1 rad = 0.01 Gy 1rem = 0.01 Sv

[0123] The Sv is the Gy dosage multiplied by a factor that includestissue damage done. For example, penetrating ionizing radiation (e.g.,gamma and beta radiation) have a factor of about 1, so 1 Sv=˜1 Gy. Alpharays have a factor of 20, so 1 Gy of alpha radiation=20 Sv.

[0124] By “effective amount of ionizing radiation” is meant an amount ofionizing radiation effective in killing, or reducing the proliferation,of abnormally proliferating cells in a subject. As used with respect tobone marrow purging, “effective amount of ionizing radiation” means anamount of ionizing radiation effective in killing, or in reducing theproliferation, of malignant cells in a bone marrow sample removed from asubject.

[0125] By “acute exposure to ionizing radiation” or “acute dose ofionizing radiation” is meant a dose of ionizing radiation absorbed by asubject in less than 24 hours. The acute dose may be localized, as inradiotherapy techniques, or may be absorbed by the subjects entire body.Acute doses are typically above 10,000 millirem (0.1 Gy), but may belower.

[0126] By “chronic exposure to ionizing radiation” or “chronic dose ofionizing radiation” is meant a dose of ionizing radiation absorbed by asubject over a period greater than 24 hours. The dose may beintermittent or continuous, and may be localized or absorbed by thesubject's entire body. Chronic doses are typically less than 10,000millirem (0.1 Gy), but may be higher.

[0127] By “effective amount of radioprotectiveN-(aryl)-2-arylethenesulfonamide compound” is meant an amount ofcompound effective to reduce or eliminate the toxicity associated withradiation in normal cells of the subject, and also to impart a directcytotoxic effect to abnormally proliferating cells in the subject. Asused with respect to bone marrow purging, “effective amount of theradioprotective N-(aryl)-2-arylethenesulfonamide compound” means anamount of compound effective to reduce or eliminate the toxicityassociated with radiation in bone marrow removed from a subject, andalso to impart a direct cytotoxic effect to malignant cells in the bonemarrow removed from the subject.

[0128] By “at risk of incurring exposure to ionizing radiation” is meantthat a subject may advertently (such as by scheduled radiotherapysessions) or inadvertently be exposed to ionizing radiation in thefuture. Inadvertent exposure includes accidental or unplannedenvironmental or occupational exposure.

DESCRIPTION OF THE FIGURES

[0129]FIG. 1 is a plot of the growth inhibition effect of(E)-4-methoxystyryl-N-4-fluorophenyl sulfonamide on the breast tumorcell line BT20, as a function of concentration.

[0130]FIG. 2 is a Western blot of BT20 cells and normal human lungfibroblast cells (HFL-1) treated with 20 micromolar(E)-4-methoxystyryl-N-4-fluorophenyl sulfonamide or vehicle (DMSO) andprobed with antibody which recognizes both full length and cleavedpoly(ADP-ribose)polymerase (PARP). The 83 kDa cleavage product is amarker for apoptosis.

DETAILED DESCRIPTION OF THE INVENTION

[0131] According to the present invention,N-(aryl)-2-arylethenesulfonamides and pharmaceutically acceptable saltsthereof selectively inhibit proliferation of cancer cells, and killvarious tumor cell types without killing normal cells. Cells are killedat concentrations where normal cells may be temporarily growth-arrestedbut not killed.

[0132] The N-(aryl)-2-arylethenesulfonamides compounds of the inventionhave been shown to inhibit the proliferation of tumor cells, and forsome compounds, induce cell death. Cell death results from the inductionof apoptosis. The compounds are believed effective against a broad rangeof tumor types, including but not limited to the following: breast,prostate, ovarian, lung, colorectal, brain (i.e, glioma) and renal. Thecompounds are also effective against leukemic cells.

[0133] The N-(aryl)-2-arylethenesulfonamides compounds are also believeduseful in the treatment of non-cancer proliferative disorders, includingbut not limited to the following: hemangiomatosis in new born, secondaryprogressive multiple sclerosis, chronic progressive myelodegenerativedisease, neurofibromatosis, ganglioneuromatosis, keloid formation,Pagets Disease of the bone, fibrocystic disease of the breast, Peroniesand Duputren's fibrosis, restenosis and cirrhosis.

[0134] The N-(aryl)-2-arylethenesulfonamides also protect normal cellsand tissues from the effects of acute and chronic exposure to ionizingradiation.

[0135] Subjects may be exposed to ionizing radiation when undergoingtherapeutic irradiation for the treatment of the above proliferativedisorders. The N-(aryl)-2-arylethenesulfonamides are effective inprotecting normal cells during therapeutic irradiation of abnormaltissues. The compounds are also believed useful in protecting normalcells during radiation treatment for leukemia, especially in the purgingof malignant cells from autologous bone marrow grafts with ionizingradiation.

[0136] According to the invention, therapeutic ionizing radiation may beadministered to a subject on any schedule and in any dose consistentwith the prescribed course of treatment, as long as theN-(aryl)-2-arylethenesulfonamide radioprotectant compound isadministered prior to the radiation. The course of treatment differsfrom subject to subject, and those of ordinary skill in the art canreadily determine the appropriate dose and schedule of therapeuticradiation in a given clinical situation.

[0137] In some embodiments of the invention, R in formula I may beselected from hydrogen and (C₁-C₆)alkyl, particularly (C₁-C₃)alkyl, andeven more particularly ethyl or methyl. In other embodiments, Q₁ and Q₂are selected from substituted and unsubstituted phenyl, particularlymono-, di- or trisubstituted phenyl. In certain embodiments, at leastone of Q₁ and Q₂ is at least trisubstituted, at least tetrasubstituted,or even pentasubstituted.

[0138] According to another embodiment of the invention of formula I, Q₁and Q₂ are optionally substituted phenyl. In some embodiments, thesubstituents are selected from halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,nitro, hydroxy and sulfamyl. In certain sub-embodiments, at least one ofQ₁ or Q₂ is substituted in at least the 4-position, or both of Q₁, andQ₂ are substituted at the 4-position. According to certain othersub-embodiments, the substitutions are selected from the groupconsisting of halogen, (C₁-C₆)alkyl and (C₁-C₆)alkoxy.

[0139] According to another sub-embodiment of the invention, a compoundhas the formula II:

[0140] wherein R₁ is selected from the group consisting of halogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano, carboxy,carboxy(C₁-C₃)alkoxy, hydroxy, (C₂-C₆)hydroxyalkyl, phosphonato, amino,(C₁-C₆)acylamino, sulfamyl, acetoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxyand trifluoromethyl; R is defined as above; and R², R³ and R⁴, areindependently selected from the group consisting of (C₁-C₆)alkoxy. Apreferred pattern of substitution for R²/R³/R⁴ is 2,4,6, that is, thecompound has the formula IIa:

[0141] wherein R¹, R², R³ and R⁴ are defined as for formula II.

[0142] In some embodiments of formula II and IIa, R¹ is selected fromthe group consisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro,hydroxy and sulfamyl.

[0143] According to another sub-embodiment, Q₁, and Q₂ are optionallysubstituted phenyl, and at least one of Q₁ or Q₂ is at leasttetrasubstituted. In other embodiments, at least one of Q₁ and Q₂ ispentasubstituted, e.g. particularly with halogen, most preferably withfluorine.

[0144] Compounds having a carbon-carbon double bond are characterized bycis-trans isomerism. Such compounds are named according to theCahn-Ingold-Prelog system, the IUPAC 1974 Recommendations, Section E:Stereochemistry, in Nomenclature of Organic Chemistry, John Wiley &Sons, Inc., New York, N.Y., 4^(th) ed., 1992, p. 127-138. Stericrelations around a double bond are designated as “Z” or “E”. Thecompounds of the present invention have the “E” configuration.

[0145] The N-(aryl)-2-arylethenesulfonamides may be prepared by one oftwo methods. In the synthesis methods to follow, reference to “aryl” isintended to include substituted and unsubstituted aryl, and alsosubstituted and unsubstituted heteroaryl.

[0146] According to Scheme 1, the arylethene A, where Q₂ is substitutedor unsubstituted aryl, is reacted with sulfonyl chloride in the presenceof a nonprotic solvent to form the corresponding arylethene sulfonylchloride B. Appropriate solvents for this reaction include, for example,dimethylformamide, chloroform and benzene. The arylethene sulfonylchloride B is then reacted in a nonprotic solvent in the presence of abase with the N-aryl compound C, wherein Q₁ is substituted orunsubstituted aryl, to obtain the desiredN-(aryl)-2-arylethenesulfonamide of formula I. The arylethene sulfonylchloride is highly reactive with N-aryl compound C, and HCl is abyproduct of the reaction. The base is present in the solvent to serveas a scavenger for the produced HCl. The same compound may serve as boththe nonprotic solvent and the base. Such dual-function solvents include,for example, pyridine, substituted pyridines, trimethylamine andtriethylamine.

[0147] According to Scheme 2, a Knoevenagel-type condensation accordingto Oliver et al., Synthesis 321-322 (May 1975) is utilized, relying onthe condensation of an arylaminosulfonylacetic acid intermediate G withan appropriate aryl aldehyde H. The entire disclosure of Oliver et al.is incorporated herein by reference.

[0148] A methyl (or ethyl) β-chlorosulfonylacetate intermediate E isprepared from methyl (or ethyl) bromoacetate (R′=methyl or ethyl). To dothis, methyl (or ethyl) bromoacetate is reacted with sodium sulfate toform the sodium sulfoacetate intermediate Na₂OSO₂CH₂CO₂R′. Potassiumsulfate may be used as a substitute for sodium sulfate. The sodiumsulfoacetate intermediate is then reacted with a chlorinating agent,preferably PCl₅, to form the methyl (or ethyl) β-chlorosulfonylacetateintermediate E. Reaction of intermediate E with the aromatic amine Cyields the arylaminosulfonylacetate intermediate F. The latter reactionis conducted in a nonprotic solvent in the presence of a base. The samecompound may serve as both the nonprotic solvent and the base. Suchdual-function solvents include, for example, pyridine, substitutedpyridines, trimethylamine and triethylamine. Thearylaminosulfonylacetate F is then converted to the correspondingarylaminosulfonylacetic acid compound G by any base capable ofhydrolyzing the ester function of F to an acid. Such bases include KOHand NaOH, for example. In the final step, the arylaminosulfonylaceticacid compound is condensed with arylaldehyde H in the presence of abasic catalyst via a Knoevenagel reaction and decarboxylation of anintermediate. Basic catalysts include, for example, pyridine andbenzylamine. The reaction yields the desiredN-(aryl)-2-arylethenesulfonamide of formula I.

[0149] The following are more detailed procedures for the preparation ofthe formula I compounds, according to either Scheme 1 (GeneralProcedure 1) or Scheme 2 (General Procedure 2).

[0150] General Procedure 1

[0151] A. Synthesis of (E)-Q₂-CH═CH—SO₂Cl

[0152] To a stirred solution of an arylethene A (0.1 mol) in dimethylformamide (30 mL), sulfuryl chloride (0.2 mol) is added dropwise for 30minutes under nitrogen atmosphere. After the addition is complete, thesolution is stirred further for 5 hours under nitrogen atmosphere. Thereaction mixture is then slowly poured into cold water (250 mL) and theprecipitated material is extracted with diethyl ether. Evaporation ofthe dried ethereal layer yields the corresponding sulfonyl chloride(E)-Q₂-CH═CH—SO₂Cl (B).

[0153] B. Condensation of (E)-Q₂-CH═CH—SO₂Cl with arylamine

[0154] The N-aryl compound C (10 mmol) and sulfonyl chloride B (10 mmol)are dissolved in 15 mL of pyridine under nitrogen. The mixture isstirred for 6 hours at room temperature, and the solvent is removed ataspirator pressure. Water (100 mL) is added to the residue and theproduct is filtered. Recrystallization of the product gives pureN-(aryl)-2-arylethenesulfonamide of formula I.

[0155] General Procedure 2

[0156] A. Synthesis of Sodium Ethyl or Methyl Sulfoacetate

[0157] A solution of ethyl or methyl bromoacetate (0.1 mol) in ethanol(50 mL) is added dropwise to a stirred cold solution of sodium sulfite(0.1 mol) in water (100 mL). After the addition is complete, the mixtureis heated briefly to 50° C. and then concentrated to dryness. The solidresidue is extracted with boiling 2:1 acetic acid/ethyl acetate (200 mL)and the hot solution is filtered and chilled overnight. The sodiummethyl or ethyl sulfoacetate obtained as a white solid is collected byfiltration.

[0158] B. Synthesis of Ethyl or Methyl Arylaminosulfonylacetate

[0159] Sodium methyl or ethyl sulfoacetate (0.1 mol) and phosphorus (V)chloride (0.11 mol) are separately pulverized and then combined in aflask equipped with a condenser and drying tube. After swirling a fewminutes, an exothermic reaction occurs. After the reaction subsides, theflask is warmed on a steam bath for 1 hour and then phosphoryl chlorideis removed in vacuo. A portion of benzene is added and the resultingsolution is filtered and evaporated to yield ethyl ormethyl-chlorosulfonyl acetate (E) solution. Benzene (50 mL) is added tothis clear oil and the solution is stirred and cooled. To this solution,an N-aryl compound C and triethylamine (10 mL) in benzene (50 mL) isadded dropwise. After the addition is complete, the mixture is warmedgently for 5 minutes, then is cooled and filtered. The filtrate iswashed with water, dilute hydrochloric acid, aqueous sodium hydrogencarbonate and aqueous sodium chloride. After drying the solvent isremoved to give crude ethyl or methyl arylaminosulfonylacetate F.Recrystallization from benzene yields a pure compound.

[0160] C. Synthesis of Arylaminosulfonylacetic Acid

[0161] The ethyl or methyl arylaminosulfonylacetate F (0.1 mol) isrefluxed for 2.5 hours in a solution of potassium hydroxide (15 g) inwater (100 mL) and ethanol (40 mL). Charcoal is added and the solutionis heated to boiling for 5 minutes, filtered, acidified withhydrochloric acid and extracted with ether. The ether extract is washedwith water, dried and evaporated to give the crudearylaminosulfonylacetic acid G which is purified by recrystallizationfrom benzene.

[0162] D. Condensation of Arylaminosulfonylacetic Acid with Arylaldehyde

[0163] A solution of the arylaminosulfonylacetic acid G (10 mmol),arylaldehyde H (10 mmol), pyridine (1 mL) and ammonium acetate (250 mg)are refluxed for 22 hours in toluene with azeotropic removal of water.The solution is cooled, washed with water, dilute hydrochloric acid andaqueous sodium hydrogen carbonate and then is extracted with 10%potassium hydroxide. The two-phase aqueous extract is washed with etherand acidified with hydrochloric acid. Evaporation of the ether extractyields crude N-(aryl)-2-arylethenesulfonamide of formula I.Recrystallization from appropriate solvent provides an analyticalsample.

[0164] N-(aryl)-2-arylethenesulfonamides according to formula I whereinthe aryl nucleus of Q₁ is substituted with the group

[0165] wherein X is sulfur or oxygen and R⁵ and R⁶ are defined as above,are prepared according to a variation of the above procedure.Accordingly, an aryl intermediate which is substituted with at least oneamino and at least one nitro group, preferably a phenyl intermediate ofthe formula III

[0166] wherein R is defined as above, and wherein the phenyl ring may befurther substituted as described above, is reacted with the sulfonylchloride B as in Scheme 1 to obtain the desiredN-(nitroaryl)-2-arylethenesulfonamide IV:

[0167] The nitro group is reduced to an amino group by hydrogenationwith a catalyst of palladium on carbon, for example, to form aminointermediate V:

[0168] Alternatively, the amine intermediate Va is prepared:

[0169] wherein R₅ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₂-C₆)heteroalkyl and substituted or unsubstitutedphenyl. The amino group is then made to react with a compound of formulaVI

[0170] wherein X is oxygen or sulfur, and R⁶ is selected from the groupconsisting of hydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substitutedaryl, unsubstituted aryl, substituted heteroaryl, unsubstitutedheteroaryl, substituted aryl-(C₁-C₃)alkyl, unsubstitutedaryl-(C₁-C₃)alkyl and (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl, to form theurea/thiourea derivative of formula VII:

[0171] The reaction may be carried out, for example, by dissolving thecompound of formula VI in deionized water and adding an approximatelyequimolar amount thereof to the intermediate V or Va dissolved in anappropriate solvent, such as glacial acetic acid. The reaction mixtureis stirred at room temperature for three hours. The reaction mixture isthen poured into deionized water and extracted 3 times with ethylacetate. The resulting combined organic layers are washed with saturatedNaHCO₃ and saturated brine. The solvent is dried over MgSO₄, filtered,and concentrated under reduced pressure. The resulting solid isrecrystalized from hot ethyl acetate/hexane, for example, to give thesulfonamide VII.

[0172] The compounds of the present invention may take the form orpharmaceutically acceptable salts. The term “pharmaceutically acceptablesalts”, embraces salts commonly used to form alkali metal salts and toform addition salts of free acids or free bases. The nature of the saltis not critical, provided that it is pharmaceutically-acceptable.Suitable pharmaceutically acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of suchinorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric,carbonic, sulfuric and phosphoric acid. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, exampleof which are formic, acetic, propionic, succinic, glycolic, gluconic,lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric,pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, algenic, beta-hydroxybutyric,salicyclic, galactaric and galacturonic acid. Suitable pharmaceuticallyacceptable base addition salts of compounds of formula I includemetallic salts made from calcium, magnesium, potassium, sodium and zincor organic salts made from N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine)and procaine. All of these salts may be prepared by conventional meansfrom the corresponding compound of formula I by reacting, for example,the appropriate acid or base with the compound of formula I.

[0173] The compounds of the invention may be administered to individuals(mammals, including animals and humans) afflicted with cancer.

[0174] The compounds are also useful in the treatment of non-cancerproliferative disorders, that is, proliferative disorders which arecharacterized by benign indications. Such disorders may also be known as“cytoproliferative” or “hyperproliferative” in that cells are made bythe body at an atypically elevated rate. Such disorders include, but arenot limited to, the following: hemangiomatosis in new born, secondaryprogressive multiple sclerosis, chronic progressive myelodegenerativedisease, neurofibromatosis, ganglioneuromatosis, keloid formation,Pagets Disease of the bone, fibrocystic disease of the breast, Peroniesand Duputren's fibrosis, restenosis and cirrhosis.

[0175] For treating proliferative disorders, the specific dose ofcompound according to the invention to obtain therapeutic benefit will,of course, be determined by the particular circumstances of theindividual patient including, the size, weight, age and sex of thepatient, the nature and stage of the disease, the aggressiveness of thedisease, and the route of administration. For example, a daily dosage offrom about 0.05 to about 50 mg/kg/day may be utilized. Higher or lowerdoses are also contemplated.

[0176] For radioprotective administration, the specific dose andschedule of N-(aryl)-2-arylethenesulfonamide to obtain theradioprotective benefit will, of course, be determined by the particularcircumstances of the individual patient including, the size, weight, ageand sex of the patient, the nature and stage of the disease beingtreated, the aggressiveness of the disease, and the route ofadministration, and the specific toxicity of the radiation. For example,a daily dosage of from about 0.01 to about 150 mg/kg/day may beutilized, more preferably from about 0.05 to about 50 mg/kg/day.Particularly preferred are doses from about 1.0 to about 10.0 mg/kg/day,for example, a dose of about 7.0 mg/kg/day. The dose may be given overmultiple administrations, for example, two administrations of 3.5 mg/kg.Higher or lower doses are also contemplated.

[0177] For radioprotective administration, theN-(aryl)-2-arylethenesulfonamide should be administered far enough inadvance of the therapeutic radiation such that the compound is able toreach the normal cells of the subject in sufficient concentration toexert a radioprotective effect on the normal cells. The compound may beadministered as much as about 24 hours, preferably no more than about 18hours, prior to administration of the radiation. In one embodiment, theN-(aryl)-2-arylethenesulfonamide is administered at least about 6-12hours before administration of the therapeutic radiation. Mostpreferably, the compound is administered once at about 18 hours andagain at about 6 hours before the radiation exposure. One or moreN-(aryl)-2-arylethenesulfonamides may be administered simultaneously, ordifferent N-(aryl)-2-arylethenesulfonamides may be administered atdifferent times during the treatment.

[0178] Where the therapeutic radiation is administered in serialfashion, it is preferable to intercalate the administration of one ormore N-(aryl)-2-arylethenesulfonamides within the schedule of radiationtreatments. As above, different N-(aryl)-2-arylethenesulfonamides may beadministered either simultaneously or at different times during thetreatment. Preferably, an about 24 hour period separates administrationof the radioprotective compound and the therapeutic radiation. Morepreferably, the administration of the radioprotectiveN-(aryl)-2-arylethenesulfonamide and the therapeutic radiation isseparated by about 6 to 18 hours. This strategy will yield significantreduction of radiation-induced side effects without affecting theanticancer activity of the therapeutic radiation.

[0179] For example, therapeutic radiation at a dose of 0.1 Gy may begiven daily for five consecutive days, with a two day rest, for a totalperiod of 6-8 weeks. One or more N-(aryl)-2-arylethenesulfonamides maybe administered to the subject 18 hours previous to each round ofradiation. It should be pointed out, however, that more aggressivetreatment schedules, i.e., delivery of a higher dosage, is contemplatedaccording to the present invention due to the protection of the normalcells afforded by the N-(aryl)-2-arylethenesulfonamides. Thus, theradioprotective effect of the compound increases the therapeutic indexof the therapeutic radiation, and may permit the physician to safelyincrease the dosage of therapeutic radiation above presently recommendedlevels without risking increased damage to the surrounding normal cellsand tissues.

[0180] The N-(aryl)-2-arylethenesulfonamides of the invention arefurther useful in protecting normal bone marrow cells from radiologictreatments designed to destroy hematologic neoplastic cells or tumorcells which have metastasized into the bone marrow. Such cells include,for example, myeloid leukemia cells. The appearance of these cells inthe bone marrow and elsewhere in the body is associated with variousdisease conditions, such as the French-American-British (FAB) subtypesof acute myelogenous leukemias (AML), chronic myeloid leukemia (CML),and acute lymphocytic leukemia (ALL). CML, in particular, ischaracterized by abnormal proliferation of immature granulocytes (e.g.,neutrophils, eosinophils, and basophils) in the blood, bone marrow,spleen, liver, and other tissues and accumulation of granulocyticprecursors in these tissues. The subject who presents with such symptomswill typically have more than 20,000 white blood cells per microliter ofblood, and the count may exceed 400,000. Virtually all CML patients willdevelop “blast crisis”, the terminal stage of the disease during whichimmature blast cells rapidly proliferate, leading to death.

[0181] Other subjects suffer from metastatic tumors, and requiretreatment with total body irradiation (TBI). Because TBI will also killthe subject's hematopoietic cells, a portion of the subject's bonemarrow is removed prior to irradiation for subsequent reimplantation.However, metastatic tumor cells are likely present in the bone marrow,and reimplantation often results in a relapse of the cancer within ashort time.

[0182] Subjects presenting with neoplastic diseases of the bone marrowor metastatic tumors may be treated by removing a portion of the bonemarrow (also called “harvesting”), purging the harvested bone marrow ofmalignant stem cells, and reimplanting the purged bone marrow.Preferably, the subject is treated with radiation or some otheranti-cancer therapy before the autologous purged bone marrow isreimplanted.

[0183] Thus, the invention provides a method of reducing the number ofmalignant cells in bone marrow, comprising the steps of removing aportion of the subject's bone marrow, administering an effective amountof at least one N-(aryl)-2-arylethenesulfonamide and irradiating thetreated bone marrow with a sufficient dose of ionizing radiation suchthat malignant cells in the bone marrow are killed. As used herein,“malignant cell” means any uncontrollably proliferating cell, such atumor cell or neoplastic cell. The N-(aryl)-2-arylethenesulfonamidesprotect the normal hematopoietic cells present in the bone marrow fromthe deleterious effects of the ionizing radiation. TheN-(aryl)-2-arylethenesulfonamides also exhibit a direct killing effecton the malignant cells. The number of malignant cells in the bone marrowis significantly reduced prior to reimplantation, thus minimizing theoccurrence of a relapse.

[0184] Preferably, each N-(aryl)-2-arylethenesulfonamide is administeredin a concentration from about 0.25 to about 100 micromolar; morepreferably, from about 1.0 to about 50 micromolar; in particular fromabout 2.0 to about 25 micromolar. Particularly preferred concentrationsare 0.5, 1.0 and 2.5 micromolar and 5, 10 and 20 micromolar. Higher orlower concentrations may also be used.

[0185] The N-(aryl)-2-arylethenesulfonamides may be added directly tothe harvested bone marrow, but are preferably dissolved in an organicsolvent such as dimethylsulfoxide (DMSO). Pharmaceutical formulations ofN-(aryl)-2-arylethenesulfonamides such as are described in more detailbelow may also be used.

[0186] Preferably, the N-(aryl)-2-arylethenesulfonamide is added to theharvested bone marrow about 20 hours prior to radiation exposure,preferably no more than about 24 hours prior to radiation exposure. Inone embodiment, the N-(aryl)-2-arylethenesulfonamide is administered tothe harvested bone marrow at least about 6 hours before radiationexposure. One or more N-(aryl)-2-arylethenesulfonamides may beadministered simultaneously, or differentN-(aryl)-2-arylethenesulfonamides may be administered at differenttimes. Other dosage regimens are also contemplated.

[0187] If the subject is to be treated with ionizing radiation prior toreimplantation of the purged bone marrow, the subject may be treatedwith one or more N-(aryl)-2-arylethenesulfonamides prior to receivingthe ionizing radiation dose, as described above.

[0188] A subject may also be exposed to ionizing radiation fromoccupation or environmental sources, as discussed in the backgroundsection. For purposes of the invention, the source of the radiation isnot as important as the type (i.e., acute or chronic) and dose levelabsorbed by the subject. It is understood that the following discussionencompasses ionizing radiation exposures from both occupational andenvironmental sources.

[0189] Subjects suffering from effects of acute or chronic exposure toionizing radiation that are not immediately fatal are said to haveremediable radiation damage. Such remediable radiation damage can bereduced or eliminated by the compounds and methods of the presentinvention.

[0190] An acute dose of ionizing radiation which may cause remediableradiation damage includes a localized or whole body dose, for example,between about 10,000 millirem (0.1 Gy) and about 1,000,000 millirem (10Gy) in 24 hours or less, preferably between about 25,000 millirem (0.25Gy) and about 200,000 (2 Gy) in 24 hours or less, and more preferablybetween about 100,000 millirem (1 Gy) and about 150,000 millirem (1.5Gy) in 24 hours or less.

[0191] A chronic dose of ionizing radiation which may cause remediableradiation damage includes a whole body dose of about 100 millirem (0.001Gy) to about 10,000 millirem (0.1 Gy), preferably a dose between about1000 millirem (0.01 Gy) and about 5000 millirem (0.05 Gy) over a periodgreater than 24 hours, or a localized dose of 15,000 millirem (0.15 Gy)to 50,000 millirem (0.5 Gy) over a period greater than 24 hours.

[0192] The invention therefore provides a method for treatingindividuals who have incurred remediable radiation damage from acute orchronic exposure to ionizing radiation, comprising reducing oreliminating the cytotoxic effects of radiation exposure on normal cellsand tissues by administering an effective amount of at least oneradioprotective N-(aryl)-2-arylethenesulfonamide compound. The compoundis preferably administered in as short a time as possible followingradiation exposure, for example between 0-6 hours following exposure.

[0193] Remediable radiation damage may take the form of cytotoxic andgenotoxic (i.e., adverse genetic) effects in the subject. In anotherembodiment, there is therefore provided a method of reducing oreliminating the cytotoxic and genotoxic effects of radiation exposure onnormal cells and tissues, comprising administering an effective amountof at least one radioprotective N-(aryl)-2-arylethenesulfonamidecompound prior to acute or chronic radiation exposure. TheN-(aryl)-2-arylethenesulfonamide may be administered, for example about24 hours prior to radiation exposure, preferably no more than about 18hours prior to radiation exposure. In one embodiment, theN-(aryl)-2-arylethenesulfonamide is administered at least about 6 hoursbefore radiation exposure. Most preferably, theN-(aryl)-2-arylethenesulfonamide is administered at about 18 and againat about 6 hours before the radiation exposure. One or moreN-(aryl)-2-arylethenesulfonamides may be administered simultaneously, ordifferent N-(aryl)-2-arylethenesulfonamides may be administered atdifferent times.

[0194] When multiple acute exposures are anticipated, theradioprotective may be administered multiple times. For example, if fireor rescue personnel must enter contaminated areas multiple times,N-(aryl)-2-arylethenesulfonamides may be administered prior to eachexposure. Preferably, an about 24 hour period separates administrationof the compound and the radiation exposure. More preferably, theadministration of N-(aryl)-2-arylethenesulfonamide and the radiationexposure is separated by about 6 to 18 hours. It is also contemplatedthat a worker in a nuclear power plant may be administered an effectiveamount of N-(aryl)-2-arylethenesulfonamide prior to beginning eachshift, to reduce or eliminate the effects of exposure to ionizingradiation.

[0195] If a subject is anticipating chronic exposure to ionizingradiation, the N-(aryl)-2-arylethenesulfonamide may be administeredperiodically throughout the duration of anticipated exposure. Forexample, a nuclear power plant worker or a soldier operating in aforward area contaminated with radioactive fallout may be given theradioprotective compound every 24 hours, preferably every 6-18 hours, inorder to mitigate the effects of radiation damage. Likewise,N-(aryl)-2-arylethenesulfonamide compound may be periodicallyadministered to civilians living in areas contaminated by radioactivefallout until the area is decontaminated or the civilians are removed toa safer environment.

[0196] As used herein, “administered” means the act of making theN-(aryl)-2-arylethenesulfonamide compound available to the subject suchthat a pharmacologic effect is obtained. For administration of drug forradioprotection, the pharmacologic effect may manifest as the absence ofexpected physiologic or clinical symptoms at a certain level ofradiation exposure. One skilled in the art may readily determine thepresence or absence of radiation-induced effects, by well-knownlaboratory and clinical methods. The N-(aryl)-2-arylethenesulfonamidecompound may thus be administered by any route which is sufficient tobring about the desired radioprotective effect in the patient.

[0197] The N-(aryl)-2-arylethenesulfonamide compounds may beadministered for therapeutic effect by any route, for example enteral(e.g., oral, rectal, intranasal, etc.) and parenteral administration.Parenteral administration includes, for example, intravenous,intramuscular, intraarterial, intraperitoneal, intravaginal,intravesical (e.g., into the bladder), intradermal, topical orsubcutaneous administration. Also contemplated within the scope of theinvention is the instillation of drug in the body of the patient in acontrolled formulation, with systemic or local release of the drug tooccur at a later time. For example, a depot ofN-(aryl)-2-arylethenesulfonamide may be administered to the patient morethan 24 hours before the administration of radiation. Preferably, atleast a portion of the compound is retained in the depot and notreleased until an about 6-18 hour window prior to the radiationexposure. For anticancer use, the drug may similarly be localized in adepot for controlled release to the circulation, or local site of tumorgrowth.

[0198] The compounds of the invention may be administered in the form ofa pharmaceutical composition, in combination with a pharmaceuticallyacceptable carrier. The active ingredient in such formulations maycomprise from 0.1 to 99.99 weight percent. By “pharmaceuticallyacceptable carrier” is meant any carrier, diluent or excipient which iscompatible with the other ingredients of the formulation and todeleterious to the recipient.

[0199] The active agent is preferably administered with apharmaceutically acceptable carrier selected on the basis of theselected route of administration and standard pharmaceutical practice.The active agent may be formulated into dosage forms according tostandard practices in the field of pharmaceutical preparations. SeeAlphonso Gennaro, ed., Remington's Pharmaceutical Sciences, 18th Ed.,(1990) Mack Publishing Co., Easton, Pa. Suitable dosage forms maycomprise, for example, tablets, capsules, solutions, parenteralsolutions, troches, suppositories, or suspensions.

[0200] For parenteral administration, the active agent may be mixed witha suitable carrier or diluent such as water, an oil (particularly avegetable oil), ethanol, saline solution, aqueous dextrose (glucose) andrelated sugar solutions, glycerol, or a glycol such as propylene glycolor polyethylene glycol. Solutions for parenteral administrationpreferably contain a water-soluble salt of the active agent. Stabilizingagents, antioxidizing agents and preservatives may also be added.Suitable antioxidizing agents include sulfite, ascorbic acid, citricacid and its salts, and sodium EDTA. Suitable preservatives includebenzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol. Thecomposition for parenteral administration may take the form of anaqueous or nonaqueous solution, dispersion, suspension or emulsion.

[0201] For oral administration, the active agent may be combined withone or more solid inactive ingredients for the preparation of tablets,capsules, pills, powders, granules or other suitable oral dosage forms.For example, the active agent may be combined with at least oneexcipient such as fillers, binders, humectants, disintegrating agents,solution retarders, absorption accelerators, wetting agents absorbentsor lubricating agents. According to one tablet embodiment, the activeagent may be combined with carboxymethylcellulose calcium, magnesiumstearate, mannitol and starch, and then formed into tablets byconventional tableting methods.

[0202] The practice of the invention is illustrated by the followingnon-limiting examples. In each of Examples 1-17, the starting(E)-Q₂-CH═CH—SO₂Cl compound was made according to part A of GeneralProcedure 1, above. The synthesized compounds are tabulated in Table 4.TABLE 4 IV

Example # X Y R 1 4-Cl H H 2 3-F, 4-OCH₃ 4-Cl H 3 4-F 4-Cl H 4 4-F4-OCH₃ H 5 3-F, 4-OCH₃ 4-OCH₃ H 6 4-F H H 7 H 4-OCH₃ CH₃ 8 3-Cl 4-Cl H 92-Cl 4-Cl H 10 4-F 4-OCH₃ H 11 4-Cl 4-F H 12 2,4,6-(OCH₃)₃ 4-OCH₃ H 132,3,4,5,6-F₅ 4-OCH₃ H 14 2,3,4,5,6-F₅ H H 15 2,3,4,5,6-F₅ 4-F H 164-SO₂NH₂ H H 17 4-SO₂NH₂ 4-OCH₃ H

EXAMPLE 1 (E)-styryl-N-4-chlorophenyl Sulfonamide

[0203] A solution of (E)-styrylsulfonyl chloride (10 mmol) and4-chloroaniline (10 mmol) was subjected to General Procedure 1, part B.The title compound, melting point 107-109° C. was obtained in 56% yield.

EXAMPLE 2 (E)-4-chlorostyryl-N-3-fluoro-4-methoxyphenyl Sulfonamide

[0204] A solution of (E)-4-chlorostyrylsulfonyl chloride (10 mmol) and3-fluoro-4methoxaniline (10 mmol) was subjected to General Procedure 1,part B. The title compound, melting point 101 - 102° C. was obtained in58% yield.

EXAMPLE 3 (E)-4-chlorostyryl-N-4-fluorophenyl Sulfonamide

[0205] A solution of (E)-4-chlorostyrylsulfonyl chloride (10 mmol) and4-fluoroaniline (10 mmol) was subjected to General Procedure 1, part B.The title compound, melting point 105-107° C., was obtained in 68.5%yield.

EXAMPLE 4 (E)-4-methoxystyryl-N-4-fluorophenyl Sulfonamide

[0206] A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) and4-fluoroaniline (10 mmol) was subjected to General Procedure 1, part B.The title compound, melting point 115-117° C., was obtained 86.4% yield.

EXAMPLE 5 (E)-4-methoxystyryl-N-3-fluoro4-methoxyphenyl Sulfonamide

[0207] A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) and3-flouro-4-methoxyaniline (10 mmol) was subjected to General Procedure1, part B. The title compound, melting point 151-153° C., was obtained80% yield.

EXAMPLE 6 (E)-styryl-N-4-fluorophenyl Sulfonamide

[0208] A solution of (E)-styrylsulfonyl chloride (10 mmol) and4-fluoroaniline (10 mmol) was subjected to General Procedure 1, part B.The title compound, melting point 83-85° C., was obtained 58.7% yield.

EXAMPLE 7 (E)-4-methoxystyryl-N-methyl-N-phenyl Sulfonamide

[0209] A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) andN-methyl aniline (10 mmol) was subjected to General Procedure 1, part B.The title compound, melting point 126-129° C., was obtained 80.9% yield.

EXAMPLE 8 (E)-4-chlorostyryl-N-3-chlorophenyl Sulfonamide

[0210] A solution of (E)-4-chlorostyrylsulfonyl chloride (10 mmol) and3-chloroaniline (10 mmol) was subjected to General Procedure 1, part B.The title compound, melting point 118-120° C., was obtained in 31.8%yield.

EXAMPLE 9 (E)-4-chlorostyryl-N-2-chlorophenyl Sulfonamide

[0211] A solution of (E)-4-chlorostyrylsulfonyl chloride (10 mmol) and2-chloroaniline (10 mmol) was subjected to General Procedure 1, part B.The title compound, melting point 107-109° C., was obtained in 57.8%yield.

EXAMPLE 10 (E)-4-methoxystyryl-N-4-fluorophenyl Sulfonamide

[0212] A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) and4- fluoroaniline (10 mmol) was subjected to General Procedure 1, part B.The title compound was obtained in 60.3% yield.

EXAMPLE 11 (E)-4-fluorostyryl-N-4-chlorophenyl Sulfonamide

[0213] A solution of (E)-4-fluorostyrylsulfonyl chloride (10 mmol) and4- chloroaniline (10mmol) was subjected to General Procedure 1, part B.The title compound, melting point 126-128° C, was obtained in 81.7%yield.

EXAMPLE 12 (E)-4-methoxystyryl-N-2,4,6-trimethoxyphenyl Sulfonamide

[0214] A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) and2,4,6- trimethoxyaniline (10 mmol) was subjected to General Procedure 1,part B. The title compound, melting point 103-106° C., was obtained in78.7% yield.

EXAMPLE 13 (E)-4-methoxystyryl-N-2,3,4,5,6-pentafluorophenyl Sulfonamide

[0215] A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) and2,3,4,5,6-pentafluoroaniline (10 mmol) was subjected to GeneralProcedure 1, part B. The title compound, melting point 58-60° C., wasobtained in 41% yield.

EXAMPLE 14 (E)-styryl-N-2,3,4,5,6-pentafluorophenyl Sulfonamide

[0216] A solution of (E)-styrylsulfonyl chloride (10 mmol) and2,3,4,5,6- pentafluoroaniline (10 mmol) was subjected to GeneralProcedure 1, part B. The title compound, melting point 145-148° C., wasobtained in 34.8% yield.

EXAMPLE 15 (E)-4-fluorostyryl-N-2,3,4,5,6-pentafluorophenyl Sulfonamide

[0217] A solution of (E)-4-fluorostyrylsulfonyl chloride (10 mmol) and2,3,4,5,6- pentafluoroaniline (10 mmol) was subjected to GeneralProcedure 1, part B. The title compound, melting point 182-184° C., wasobtained in 36.1 % yield.

EXAMPLE 16 (E)-styryl-N-4-sulfamylphenyl Sulfonamide.

[0218] A solution of (E)-styrylsulfonyl chloride (10 mmol) andsulfanilamide (10 mmol) was subjected to General Procedure 1, part B.The title compound, melting point 171-173° C., was obtained in 80%yield.

EXAMPLE 17 (E)-4-methoxystyryl-N-4-sulfamylphenyl Sulfonamide

[0219] A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) andsulfanilamide (10 mmol) was subjected to General Procedure 1, part B.The title compound, melting point 181-183° C., was obtained in 46.2%yield.

[0220] The following additional compounds, tabulated in Tables 5 and 6,are made by subjecting a solution containing a 10 mmolar concentrationof the two indicated reactants to either General Procedure 1, part B(Examples Nos. 18, 19, 21-23, 26, 27, 30, 33, 36, 39, 41, 44, 47-50, 55,59, 61, 64 and 65) or General Procedure 2, part D (Examples Nos. 20, 24,25, 28, 29, 31, 32, 34, 35, 37, 38, 40, 42, 43, 45, 46, 51-54, 56-58,60, 62, 63, 66 and 67). TABLE 5 IV

Ex. X Y Reactants Product 18 2-Cl 2,3,4,5,6-F₅ pentafluorostyrylsulfonylchloride and (E)-pentafluorostyryl-N-2- 2-chloroaniline chlorophenylsulfonamide 19 4-F 2,3,4,5,6-F₅ pentafluorostyrylsulfonyl chloride and(E)-pentafluorostyryl-N-4- 4-fluoroaniline sulfonamide fluorophenylsulfonamide 20 4-Br 2,3,4,5,6-F₅ 4-bromophenylaminosulfonylacetic acid(E)-pentafluorostyryl-N-4- and pentafluorobenzaldehyde bromophenylsulfonamide 21 2-F, 4-Cl 2,3,4,5,6-F₅ pentafluorostyrylsulfonyl chlorideand (E)-pentafluorostyryl-N-2- 2-fluoro-4-chloroanilinefluoro-4-chlorophenyl sulfonamide 22 4-OCH₃ 2,3,4,5,6-F₅pentafluorostyrylsulfonyl chloride and (E)-pentafluorostyryl-N-4-4-methoxyaniline methoxyphenyl sulfonamide 23 3-F, 4- 2,3,4,5,6-F₅pentafluorostyrylsulfonyl chloride and (E)-pentafluorostyryl-N-3- OCH₃3-fluoro-4-methoxyaniline fluoro-4-methoxyphenyl sulfonamide 24 2,3,4-2,3,4,5,6-F₅ 2,3,4- (E)-pentafluorostyryl-N- (OCH₃)₃trimethoxyphenylaminosulfonylacetic 2,3,4-trimethoxyphenyl acid andpentafluorobenzaldehyde sulfonamide 25 4-OH 2,3,4,5,6-F₅4-hydroxyphenylaminosulfonylacetic (E)-pentafluorostyryl-N-4- acid andpentafluorobenzaldehyde hydroxyphenyl sulfonamide 26 4-NO₂ 2,3,4,5,6-F₅pentafluorostyrylsulfonyl chloride and (E)-pentafluorostyryl-N-4-4-nitroaniline nitrophenyl sulfonamide 27 4-SO₂NH₂ 2,3,4,5,6-F₅pentafluorostyrylsulfonyl chloride and (E)-pentafluorostyryl-N-4-4-sulfanilamide sulfamylphenyl sulfonamide 28 3-F, 4- 2,3,4,5,6-F₅3-fluoro-4- (E)-pentafluorostyryl-N- OCH₃methoxyphenylaminosulfonylacetic acid phenyl sulfonamide andpentafluorobenzaldehyde 29 2,4,6- 2,3,4,5,6-F₅ 2,4,6-(E)-pentafluorostyryl-N-3- (OCH₃)₃ trimethoxyphenylaminosulfonylaceticfluoro-4-methoxyphenyl acid and pentafluorobenzaldehyde sulfonamide 302,3,4,5,6- 2,3,4,5,6-F₅ pentafluorostyrylsulfonyl chloride and(E)-pentafluorostyryl-N- F₅ pentafluoroaniline pentafluorophenylsulfonamide 31 2-Cl 2,4,6- 2-chlorophenylaminosulfonylacetic acid(E)-2,4,6-trimethoxystyryl- (OCH₃)₃ and 2,4,6-trimethoxybenzaldehydeN-2-chlorophenyl sulfonamide 32 4-F 2,4,6-4-bromophenylaminosulfonylacetic acid (E)-2,4,6-trimethoxystyryl-(OCH₃)₃ and 2,4,6-trimethoxybenzaldehyde N-4-fluorophenyl sulfonamide 334-Br 2,4,6- 2,4,6-trimethoxystyrylsulfonyl chloride(E)-2,4,6-trimethoxystyryl- (OCH₃)₃ and 4-bromoaniline N-4-bromophenylsulfonamide 34 2-F, 4-Cl 2,4,6- 2-fluoro-4- (E)-2,4,6-trimethoxystyryl-(OCH₃)₃ chlorophenylaminosulfonylacetic acid N-2-fluoro-4-chlorophenyland 2,4,6-trimethoxybenzaldehyde sulfonamide 35 4-OCH₃ 2,4,6-4-methoxyphenylaminosulfonylacetic (E)-2,4,6-trimethoxystyryl- (OCH₃)₃acid and 2,4,6-trimethoxybenzaldehyde N-4-methoxyphenyl sulfonamide 363-F, 4- 2,4,6- 2,4,6-trimethoxystyrylsulfonyl chloride(E)-2,4,6-trimethoxystyryl- OCH₃ (OCH₃)₃ and 3-fluoro-4-methoxyanilineN-3-fluoro-4-methoxyphenyl sulfonamide 37 2,3,4- 2,4,6- 2,3,4-(E)-2,4,6-trimethoxystyryl- (OCH₃)₃ (OCH₃)₃trimethoxyphenylaminosulfonylacetic N-2,3,4-trimethoxyphenyl acid and2,4,6-trimethoxybenzaldehyde sulfonamide 38 4-OH 2,4,6-4-hydroxyphenylaminosulfonylacetic (E)-2,4,6-trimethoxystyryl- (OCH₃)₃acid and 2,4,6-trimethoxybenzaldehyde N-4-hydroxyphenyl sulfonamide 394-H₂PO₄ 2,4,6- 2,4,6-trimethoxystyrylsulfonyl chloride(E)-2,4,6-trimethoxystyryl- (OCH₃)₃ and 4-phosphonatoanilineN-4-phosphonatophenyl sulfonamide 40 4-NO₂ 2,4,6-4-nitrophenylaminosulfonylacetic acid (E)-2,4,6-trimethoxystyryl-(OCH₃)₃ and 2,4,6-trimethoxybenzaldehyde N-4-nitrophenyl sulfonamide 412,4,6- 2,4,6- 2,4,6-trimethoxystyrylsulfonyl chloride(E)-2,4,6-trimethoxystyryl- (OCH₃)₃ (OCH₃)₃ and 2,4,6-trimethoxyanilineN-2,4,6-trimethoxyphenyl sulfonamide 42 2,3,4,5,6- 2,4,6- 2,3,4,5,6-(E)-2,4,6-trimethoxystyryl- F₅ (OCH₃)₃pentafluorophenylaminosulfonylacetic N-pentafluorophenyl acid and2,4,6-trimethoxybenzaldehyde sulfonamide 43 4-SO₂NH₂ 2,4,6-4-sulfamylphenylaminosulfonylacetic (E)-2,4,6-trimethoxystyryl- (OCH₃)₃acid and 2,4,6-trimethoxybenzaldehyde N-4-sulfamylphenyl sulfonamide 442,3,4,5,6- 2,4,6- 2,4,6-trimethoxystyrylsulfonyl chloride(E)-2,4,6-trimethoxystyryl- F₅ (OCH₃)₃ and pentafluoroanilineN-pentafluoro sulfonamide 45 4-OCH₃ 3,4,5-4-methoxyphenylaminosulfonylacetic (E)-3,4,5-trimethoxystyryl- (OCH₃)₃acid and 3,4,5-trimethoxybenzaldehyde N-4-methoxyphenyl sulfonamide 463-F, 4- 3,4,5- 3-fluoro-4- (E)-3,4,5-trimethoxystyryl- OCH₃ (OCH₃)₃methoxyphenylaminosulfonylacetic acid N-3-fluoro-4-methoxyphenyl and3,4,5-trimethoxybenzaldehyde sulfonamide 47 2,3,4- 3,4,5-3,4,5-trimethoxystyrylsulfonyl chloride (E)-3,4,5-trimethoxystyryl-(OCH₃)₃ (OCH₃)₃ and 2,3,4-trimethoxyaniline N-2,3,4-trimethoxyphenylsulfonamide

[0221] TABLE 6

Ex. Q₁ Q₂ Reactants Product 48 2-benzothiazolyl pentafluorophenylpentafluorostyryl-sulfonyl chloride and 2-(E)-pentafluorostyryl-N-3-benzothiazolylsulfonamide aminobenzathiazole49 2-benzoxazolyl 2,4,6- 2,4,6-trimethoxystyrylsulfonyl chloride and 2-(E)-2,4,6-trimethoxystyryl-N-3-benzoxazolylsulfonamide trimethoxyphenylaminobenzoxazole 50 2-thiazolyl 4-methoxyphenyl 4-methoxystyrylsulfonylchloride and 2- (E)-4-methoxystyryl-N-3-2-thiazolylsulfonamideaminothiazole 51 3-indolyl pentafluorophenyl3-indolylaminosulfonylacetic acid and (E)-pentafluorostyryl-N-3-indolylsulfonamide pentafluorobenzaldehyde 52 4-indolyl 2,4,6-4-indolylaminosulfonylacetic acid and 2,4,6-(E)-2,4,6-trimethoxystyryl-N-4-indolyl sulfonamide trimethoxyphenyltrimethoxybenzaldehyde 53 5-indolyl 3-fluoro-4-5-indolylaminosulfonylacetic acid and 3-fluoro-(E)-3-fluoro-4-methoxystyryl-N-5-indolyl sulfonamide methoxyphenyl4-methoxybenzaldehyde 54 3-isoxazolyl 3-indolyl3-isoxazolylaminosulfonylacetic acid and 3- (E)-N-3-isoxazolyl-3-indolylethenesulfonamide indolylcarbaldehyde 55 3-quinolinyl 4-pyridinyl3-Aminoquinoline and 4-pyridine ethenyl (E)-N-3-quinolinyl-4-pyridylethenesulfonamide sulfonylchloride 56 3-(1,2,3-triazolyl)pentafluorophenyl 3-(1,2,3-triazolyl)aminosulfonylacetic acid and(E)-N-1,2,3-triazolyl- pentafluorobenzaldehyde2,3,4,5,6-pentafluorostyrylsulfonamide 57 2,4,6- 5-indolyl2,4,6-trimethoxyphenylaminosulfonyl-acetic(E)-N-2,4,6-trimethoxyphenyl-5-indolyl trimethoxyphenyl acid and5-indolylcarboxaldehyde ethenesulfonamide 58 2-imidazolylpentafluorophenyl 2-imidazolylaminosulfonylacetic acid and(E)-N-2-imidazolyl-2,3,4,5,6- pentafluorobenzaldehydepentafluorostyrylsulfonamide 59 5-isothiazolyl 2-pyridinyl5-aminoisothiazole and 2-pyridene ethenyl (E)-N-5-thiazolyl-2-pyridylethenesulfonamide sulfonylchloride 60 3-pyrazolyl 2,4,6-3-pyrazolylaminosulfonylacetic acid and 2,4,6-(E)-N-3-pyrazolyl-2,4,6-trimethoxystyryl sulfonamide trimethoxyphenyltrimethoxybenzaldehyde 61 4-cyano-3- pentafluorophenyl4-cyano-3-pyrazolylaminosulfonylacetic acid(E)-N-4-cyano-3-pyrazolyl-pentafluorostyrylsulfonamide pyrazolyl andpentafluorobenzaldehyde 62 4-methoxyphenyl 3-quinolinyl4-methoxyphenylaminosulfonylacetic acid and(E)-N-4-methoxyphenyl-3-quinolinyl ethenesulfonamide3-quinolinylcarboxaldehyde 63 3-fluoro-4- 5-indolyl3-fluoro-4-methoxyphenylaminosulfonyl-acetic(E)-N-3-fluoro-4-methoxyphenyl-5-indolyl methoxyphenyl acid and5-indolylcarboxaldehyde ethenesulfonamide 64 2,3,4- 3-pyrazolyl2,3,4-trimethoxyphenylaminosulfonyl-acetic(E)-N-2,3,4-trimethoxyphenyl-3-pyrazolyl trimethoxyphenyl acid and3-pyrazolecarboxaldehyde ethenesulfonamide 65 4-hydroxyphenyl4-pyridinyl 4-hydroxyaniline and 4-pyridine ethenyl(E)-N-4-hydroxyphenyl-4-pyridyl ethenesulfonamide sulfonylchloride 66pentafluorophenyl 4-quinolinyl pentafluorophenylaminosulfonylacetic acidand (E)-N-pentafluorophenyl-4-quinolinyl ethenesulfonamide4-quinolinylcarboxaldehyde 67 2,4,6- 2-imidazolyl2,4,6-trimethoxyphenylaminosulfonyl-acetic(E)-N-2,4,6-trimethoxyphenyl-2-imidazolyl trimethoxyphenyl acid and2-imidazolylcarboxaldehyde ethenesulfonamide

EXAMPLE 68 Effect of N-(Aryl)-2-Arylethenesulfonamides on Tumor CellLines.

[0222] The effect of the N-(aryl)-2-arylethenesulfonamides on normalfibroblasts and on tumor cells was determined by the assay described byLatham et al, Oncogene 12:827-837 (1996). Normal diploid lung humanfibroblasts (HFL-1) or tumor cells (prostate, colorectal, breast, glial,pancreatic ovarian or leukemic) were plated in 6-well dishes at a celldensity of 1.0 ×10⁵ cells per 35-mm² well. The plated cells were treated24 hours later with various concentrations ofN-(aryl)-2-arylethenesulfonamide dissolved in dimethyl sulfoxide (DMSO).The total number of viable cells was determined 96 hours later bytrypsinizing the wells and counting the number of viable cells, asdetermined by trypan blue exclusion, using a hemacytometer. Eachcompound tested (Exs. 1-17) inhibited cell proliferation when tested ata concentration of 30 micromolar. Some compounds inhibited proliferationat lower concentrations. Certain compounds induced cell death, atconcentrations from 1 to 10 micromolar. Normal HFL cells were treatedwith the same compounds under the same conditions of concentration andtime. The normal cells displayed growth inhibition but no appreciablecell death.

EXAMPLE 69 Determination of GI₅₀

[0223] A dose response curve was plotted for the tumor growth inhibitoryeffect of (E)-4-methoxystyryl-N-4-fluorophenyl sulfonamide on theestrogen-unresponsive breast cell line BT-20 (FIG. 1). The GI₅₀ (theconcentration of drug resulting in 50% net loss of growth inhibition)was determined as 10 μM. In contrast, the normal fibroblast line HFL-1exhibited a GI₅₀ of 50 μM. The (E)-4-methoxystyryl-N-4-fluorophenylsulfonamide GI₅₀ for the same compound against the cell lines listed inTable 7 was determined in the same manner. TABLE 7 GI₅₀ for growthinhibition effect of (E)-4-methoxystyryl-N-4- fluorophenyl sulfonamideon various cell lines CELL LINE TUMOR TYPE GI₅₀ (μM) DU145 Prostate 10PC-3 Prostate 20 LNCAP Prostate 20 DLD-1 Colo-rectal 15 HCT-116Colo-rectal 20 COLO-320 Colo-rectal 5 BT2O Breast 10 SK-br-3 Breast 30U87 Glioblastoma 20 MIA-PaCa-2 Pancreatic 7 SK-ov-3 Ovarian 15 CEMLeukemic 30 HFL-1 Normal diploid lung 50

[0224] The GI₅₀ of (E)-4-methoxystyryl-N-3-fluoro-4-methoxyphenylsulfonamide was determined for the following cell lines: BT20, DU145,H157 and DLD-1. The GI₅₀ for each cell line was in essential agreementwith the GI₅₀ determined for (E)-4-methoxystyryl-N-4-fluorophenylsulfonamide in the same cell line.

EXAMPLE 70 Induction of Apoptosis in Tumor Cells

[0225] The following assay demonstrates the apoptotic activity of thecompounds of the invention against tumor cells.

[0226] The caspases and the ICE-family proteases are cysteine proteaseswhich are activated during apoptosis (Patel et al., FASEB 10:587-597,1996). The cleavage of poly(ADP-ribose) polymerase (PARP), which is atarget of caspase-3, apopain, and several other activated proteases, isa widely used and accepted marker for apoptosis (Nicholson et al.,Nature 376(6533):37-43, 1995; Lippke et al., J. Biol. Chemistry271:1825, 1996). For this assay, BT20 cells, an estrogen receptornegative breast carcinoma, and HFL-1 cells, normal lung fibroblasts,were treated with either (E)-4-methoxystyryl-N-4-fluorophenylsulfonamide at a final concentration of 20 μM or dimethyl sulfoxide(DMSO) for 96 hours. The cells were then lysed in RIPA buffer and 100 μgof total cellular protein from each sample was resolved on a 10%SDS-polyacrylamide gel. The proteins were then Western blotted ontoPROTRAN filter paper (S/S) and the filter was then probed with antibody(Boehringer Mannheim) specific for PARP. This antibody recognizes boththe 116 kDa full length PARP and the 83 kDa cleaved product. Theresults, set forth in FIG. 2, show that a 96 hour treatment with thetest compound specifically activated caspases in the treated breastcarcinoma cell line and not in the normal cell line. The western blotclearly shows that only the test compound-treated BT20 cells had thepresence of the 83 kDa PARP cleavage product. The HFL-1 cells treated ina similar manner showed no cleavage of the full length PARP. The BT20cells treated with DMSO for the same amount of time also had noactivation of the apoptotic pathway. These results show that thecompounds of the invention selectively kill cancer cells by activatingthe apoptotic pathway as indicated by the activation of the cysteineproteases, a molecular marker for apoptosis. Cells which are nottumorigenic do not undergo apoptosis but become growth arrested atconcentrations significantly higher than the concentration necessary fortumor cell death.

EXAMPLE 71 Radioprotective Effects of N-Aryl-2-Arylethenesulfonamides onCultured Normal Cells

[0227] The radioprotective effects of (a) styryl-N-phenylsulfonamide,(b) 4- methoxystyryl-N-flourophenylsulfonamide; (c)styryl-N-methyl-N-phenyl-sulfonamide and (d)4-methoxystyryl-N-2,4,6-trimethoxyphenylsulfonamide were evaluated oncultured normal cells as follows.

[0228] HFL-1 cells, which are normal diploid lung fibroblasts, wereplated into 24 well dishes at a cell density of 3000 cells per 10 mm² inDMEM completed with 10% fetal bovine serum and antibiotics. The testcompounds were added to the cells 24 hours later in selectconcentrations from 2.5 μM and 10.0 μM, inclusive, using DMSO as asolvent. Control cells were treated with DMSO alone. The cells wereexposed to the test compound or DMSO for 24 hours.

[0229] The cells were then irradiated with 10 Gy (gray) of ionizingradiation (IR) using a J. L. Shepherd Mark I, Model 30-1 Irradiatorequipped with ¹³⁷cesium as a source. After irradiation, the medium onthe test and control cells was removed and replaced with fresh growthmedium without the test compounds or DMSO. The irradiated cells wereincubated for 96 hours and then duplicate wells were trypsinized andreplated onto 100 mm² tissue culture dishes. The replated cells weregrown under normal conditions with one change of fresh medium for 2weeks. The number of colonies from each 100 mm² culture dish, whichrepresents the number of surviving cells, was determined by staining thedishes as described below.

[0230] In order to visualize and count the colonies derived from theclonal outgrowth of individual protected cells, the medium was removedand the plates were washed one time with room temperature phosphatebuffered saline. The cells were stained with a 1:10 diluted ModifiedGeimsa staining solution (Sigma) for 20 minutes. The stain was removed,and the plates were washed with tap water. The plates were air dried,the number of colonies from each plate was counted and the average fromduplicate plates was determined. Each compound provided radioprotectiveactivity of between 4- and 6-fold at the concentrations tested. Foldprotection was determined by dividing the average number of coloniesfrom the test plates by the average number of colonies counted on thecontrol plates.

EXAMPLE 72 Protection of Mice from Radiation Toxicity by Pre-Treatmentwith N-Aryl-2-Arylethenesulfonamides

[0231] C57 black mice age 10-12 weeks (Taconic) are divided intotreatment groups of 10 mice each and given intraperitoneal injections of200 micrograms of N-aryl-2-arylethenesulfonamide dissolved in DMSO (a 10mg/Kg dose, based on 20 g mice). The injections are given 18 and 6 hoursbefore irradiation with 8 Gy gamma radiation. A control group of 10animals receives 8 Gy gamma radiation alone. Mortality of control andexperimental groups is assessed for 40 days after irradiation.

EXAMPLE 73 Radioprotective Effect of N-Aryl-2-Arylethenesulfonamides inMice When Given After Radiation Exposure

[0232] C57 B6/J mice age 10-12 weeks (Taconic) are divided intotreatment groups and one control group of 10 mice each. Each treatmentgroup receives intraperitoneal injections of 200 micrograms ofN-aryl-2-arylethenesulfonamide dissolved in DMSO (a 10 mg/Kg dose, basedon 20 g mice) 15 minutes after irradiation with 8 Gy gamma radiation.The control group receives 8 Gy gamma radiation alone. Mortality ofcontrol and treatment groups are assessed for 40 days after irradiation.

EXAMPLE 74 Effect of Exposure to Ionizing Radiation on Normal andMalignant Hematopoietic Progenitor Cell Growth After Pretreatment withN-Aryl-2-Arylethenesulfonamides

[0233] The effect of ionizing radiation on normal and malignanthematopoietic progenitor cells which are pretreated withN-aryl-2-arylethenesulfonamides is investigated by assessing cloningefficiency and development of the pretreated cells after irradiation.

[0234] To obtain hematopoietic progenitor cells, human bone marrow cells(BMC) or peripheral blood cells (PB) are obtained from normal healthy,or acute or chronic myelogenous leukemia (AML, CML), volunteers byFicoll-Hypaque density gradient centrifugation, and are partiallyenriched for hematopoietic progenitor cells by positively selectingCD34⁺ cells with immunomagnetic beads (Dynal A. S., Oslo, Norway). TheCD34⁺ cells are suspended in supplemented alpha medium and incubatedwith mouse anti-HPCA-I antibody in 1:20 dilution, 45 minutes, at 4° C.with gentle inverting of tubes. Cells are washed ×3 in supplementedalpha medium, and then incubated with beads coated with the Fc fragmentof goat anti-mouse IgG₁ (75 μl of immunobeads/ 10⁷ CD34⁺ cells). After45 minutes of incubation (4° C.), cells adherent to the beads arepositively selected using a magnetic particle concentrator as directedby the manufacturer.

[0235] 2×10⁴ CD34⁺ cells are incubated in 5 ml polypropylene tubes(Fisher Scientific, Pittsburgh, Pa.) in a total volume of 0.4 ml ofIscove's modified Dulbecco's medium (IMDM) containing 2% human AB serumand 10 mM Hepes buffer. An N-aryl-2-arylethenesulfonamide, for examplestyryl-N-phenylsulfonamide; 4-methoxystyryl-N-flourophenylsulfonamide;styryl-N-methyl-N-phenylsulfonamide; or4-methoxystyryl-N-2,4,6-trimethoxyphenyl-sulfonamide at three differentconcentrations (2.5 μM, 5.0 μM and 10.0 μM) in DMSO are added separatelyto the cells. Control cells received DMSO alone. The cells are incubatedfor 20-24 hours and irradiated with 5 Gy or 10 Gy of ionizing radiation.Immediately after irradiation, the medium is removed and replaced withfresh medium without the test compound or DMSO. Twenty-four hours afterirradiation, the treatment and control cells are prepared for plating inplasma clot or methylcellulose cultures. Cells (1×10⁴ CD34⁺ cells perdish) were not washed before plating.

[0236] Assessment of the cloning efficiency and development of thetreated hematopoietic progenitor cells are carried out essentially asreported in Gewirtz et al., Science 242, 1303-1306 (1988), thedisclosure of which is incorporated herein by reference.

EXAMPLE 75 Bone Marrow Purging with Ionizing Radiation AfterPretreatment with N-Aryl-2-Arylethenesulfonamides

[0237] Bone marrow is harvested from the iliac bones of a subject undergeneral anesthesia in an operating room using standard techniques.Multiple aspirations are taken into heparinized syringes. Sufficientmarrow is withdrawn so that the subject will be able to receive about4×10⁸ to about 8×10⁸ processed marrow cells per kg of body weight. Thus,about 750 to 1000 ml of marrow is withdrawn. The aspirated marrow istransferred immediately into a transport medium (TC-199, Gibco, GrandIsland, N.Y.) containing 10,000 units of preservative-free heparin per100 ml of medium. The aspirated marrow is filtered through threeprogressively finer meshes to obtain a cell suspension devoid ofcellular aggregates, debris and bone particles. The filtered marrow isthen processed further into an automated cell separator (e.g., Cobe 2991Cell Processor) which prepares a “buffy coat” product, (i.e., leukocytesdevoid of red cells and platelets). The buffy coat preparation is thenplaced in a transfer pack for further processing and storage. It may bestored until purging in liquid nitrogen using standard procedures.Alternatively, purging can be carried out immediately, then the purgedmarrow may be stored frozen in liquid nitrogen until it is ready fortransplantation.

[0238] The purging procedure is carried out as follows. Cells in thebuffy coat preparation are adjusted to a cell concentration of about2×10⁷/ml in TC-199 containing about 20% autologous plasma. AnN-aryl-2-arylethenesulfonamide; for example 2.5 to 10 micromolar ofeither styryl-N-phenylsulfonamide;4-methoxystyryl-N-flourophenylsulfonamide;styryl-N-methyl-N-phenylsulfon-amide; or4-methoxystyryl-N-2,4,6-trimethoxyphenylsulfonamide in DMSO is added tothe transfer packs containing the cell suspension and incubated in a 37°C. water bath for 20-24 hours with gentle shaking. The transfer packsare then exposed to 5-10 Gy ionizing radiation. Recombinant humanhematopoietic growth factors, e.g., rH IL-3 or rH GM-CSF, may be addedto the suspension to stimulate growth of hematopoietic neoplasms andthereby increase their sensitivity to ionizing radiation.

[0239] The cells may then either be frozen in liquid nitrogen or washedonce at 4° C. in TC-199 containing about 20% autologous plasma. Washedcells are then infused into the subject. Care must be taken to workunder sterile conditions wherever possible and to maintain scrupulousaseptic techniques at all times.

[0240] All references cited herein are incorporated by reference. Thepresent invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof and,accordingly, reference should be made to the appended claims, ratherthan to the foregoing specification, as indication the scope of theinvention.

1. A compound of the formula:

wherein: Q₁ and Q₂ are independently selected from the group consistingof substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl; R is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,(C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl(C₁-C₃)alkyl,substituted heteroaryl(C₁-C₃)alkyl and unsubstitutedheteroaryl(C₁-C₃)alkyl; wherein the substituents for the substitutedaryl and substituted heteroaryl groups comprising Q₁ are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy, trifluoromethyl and

wherein: X is oxygen or sulfur, R⁵ is selected from the group consistingof hydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted phenyl, andunsubstituted phenyl, and R⁶ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl-(C₁-C₃)alkyl and(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl; wherein the substituents for thesubstituted aryl and substituted heteroaryl groups comprising Q_(2,) andthe substituents for the substituted aryl and substituted heteroarylgroups comprising or included within R, R⁵ and R⁶, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆ alkoxy) and trifluoromethyl;provided, that when R is hydrogen: (a) when Q₁ is unsubstituted phenyl,Q₂ is other than dimethoxyphenyl, 2-methylphenyl, 2-chlorophenyl,4-chlorophenyl, 4-N,N-dimethylaminophenyl, 4-methylphenyl,4-methoxyphenyl, 4-nitrophenyl, 3-methoxy-4-hydroxyphenyl, unsubstitutedphenyl, unsubstituted pyrenyl, unsubstituted benzodioxolyl,unsubstituted 1-naphthyl and unsubstituted 2-thienyl; (b) when Q₁ is2,4-dinitrophenyl, Q₂ is other than 4-methylphenyl, 4-methoxyphenyl,4-nitrophenyl, 4-bromophenyl, 3,4-dichlorophenyl, unsubstituted phenylor unsubstituted 1-naphthyl; (c) when Q₁ is 3-hydroxyphenyl, Q₂ is otherthan 2-nitrophenyl, or 3-nitrophenyl; (d) when Q₁ is2-methyl-5-hydroxyphenyl, Q₂ is other than 4-nitrophenyl; (e) when Q₁ isunsubstituted 2-pyridyl, Q₂ is other than 3-methoxy-4-hydroxyphenyl; and(f) when Q₂ is unsubstituted phenyl, Q₁ is other than 2-hydroxyphenyl,2-aminophenyl, 3,4-dichlorophenyl or unsubstituted 2-pyridyl; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, provided: (a) when Q₁ is unsubstituted phenyl, Q₂ is other thandialkoxyphenyl, 2-alkylphenyl, 2-halophenyl, 4-halophenyl,4-N,N-dialkylaminophenyl, 4-alkylphenyl, 4-alkoxyphenyl, 4-nitrophenyl,3-alkoxy-4-hydroxyphenyl, unsubstituted phenyl, unsubstituted pyrenyl,unsubstituted benzodioxolyl, unsubstituted 1-naphthyl and unsubstituted2-thienyl; (b) when Q₁ is 2,4-dinitrophenyl, Q₂ is other than4-alkylphenyl, 4-alkoxyphenyl, 4-nitrophenyl, 4-halophenyl,3,4-dihalophenyl, unsubstituted phenyl or unsubstituted 1-naphthyl; (c)when Q₁ is 3-hydroxyphenyl, Q₂ is other than nitrophenyl; (d) when Q₁ is2-methyl-5-hydroxyphenyl, Q₂ is other than 4-nitrophenyl; (e) when Q₁ isunsubstituted 2-pyridyl, Q₂ is other than 3-methoxy-4-hydroxyphenyl; and(f) when Q₂ is unsubstituted phenyl, Q₁ is other than 2-hydroxyphenyl,2-aminophenyl, 3,4-dihalophenyl or unsubstituted 2-pyridyl; or apharmaceutically acceptable salt thereof.
 3. A compound according toclaim 2, provided: when R is hydrogen: (i) Q₁ may not be dinitrophenyl;(ii) Q₂ may not be dinitrophenyl; and (iii) when Q₂ is mononitrophenyl:Q₁ is other than substituted phenyl, or Q₁ is substituted phenyl whereinat least the 4-position is substituted, and the substituent is otherthan hydroxy; or a pharmaceutically acceptable salt thereof.
 4. Acompound according to claim 1 wherein R is hydrogen or (C₁-C₆)alkyl. 5.A compound according to claim 4 wherein Q₁ and Q₂ are optionallysubstituted phenyl.
 6. A compound according to claim 5 wherein at leastone of Q₁ and Q₂ is substituted in at least the 4-position.
 7. Acompound according to claim 6 wherein the substituents are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, hydroxy and sulfamyl.
 8. A compound according toclaim 7 wherein the compound is (E)-styryl-N-4-sulfamylphenylsulfonamide, or a pharmaceutically acceptable salt thereof.
 9. Acompound according to claim 7 wherein the compound is(E)-styryl-N-4-chlorophenyl sulfonamide or (E)-styryl-N-4-fluorophenylsulfonamide, or a pharmaceutically acceptable salt thereof.
 10. Acompound according to claim 7 wherein the compound is(E)-4-methoxystyryl-N-methyl-N-phenyl sulfonamide, or a pharmaceuticallyacceptable salt thereof.
 11. A compound according to claim 7 wherein thecompound is (E)-4-chlorostyryl-N-3-chlorophenyl sulfonamide, or apharmaceutically acceptable salt thereof.
 12. A compound according toclaim 7 wherein the compound is (E)-4-chlorostyryl-N-2-chlorophenylsulfonamide, or a pharmaceutically acceptable salt thereof.
 13. Acompound according to claim 6 wherein Q₁ and Q₂ are both independentlysubstituted in at least the 4-position.
 14. A compound according toclaim 13 wherein the substituents are independently selected from thegroup consisting of halogen, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, nitro,hydroxy and sulfamyl.
 15. A compound according to claim 14 wherein thecompound is (E)-4-methoxystyryl-N-4-sulfamylphenyl sulfonamide, or apharmaceutically acceptable salt thereof.
 16. A compound according toclaim 14 wherein the compound is(E)-4-chlorostyryl-N-3-fluoro-4-methoxyphenyl sulfonamide, or apharmaceutically acceptable salt thereof.
 17. A compound according toclaim 14 wherein the compound is (E)-4-chlorostyryl-N-4-fluorophenylsulfonamide, or a pharmaceutically acceptable salt thereof.
 18. Acompound according to claim 14 wherein the compound is(E)-4-methoxystyryl-N-4-fluorophenyl sulfonamide, or a pharmaceuticallyacceptable salt thereof.
 19. A compound according to claim 14 whereinthe compound is (E)-4-methoxystyryl-N-3-fluoro-4-methoxyphenylsulfonamide, or a pharmaceutically acceptable salt thereof.
 20. Acompound according to claim 14 wherein the compound is(E)-4-methoxystyryl-N-4-fluorophenyl sulfonamide, or a pharmaceuticallyacceptable salt thereof.
 21. A compound according to claim 14 whereinthe compound is (E)-4-fluorostyryl-N-4-chlorophenyl sulfonamide, or apharmaceutically acceptable salt thereof.
 22. A compound according toclaim 14 wherein the compound is(E)-4-methoxystyryl-N-2,4,6-trimethoxyphenyl sulfonamide, or apharmaceutically acceptable salt thereof.
 23. A compound according toclaim 6 of the formula:

wherein R is hydrogen or (C₁-C₆)alkyl; R₁ is selected from the groupconsisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano,carboxy, carboxy(C₁-C₃)alkoxy, hydroxy, (C₂-C₆)hydroxyalkyl,phosphonato, amino, (C₁-C₆)acylamino, sulfamyl, acetoxy,di(C₁-C₆)alkylamino(C₂-C₆)alkoxy and trifluoromethyl; and R², R³ andR^(4,) are independently selected from the group consisting of(C₁-C₆)alkoxy.
 24. A compound according to claim 23 of the formula:

wherein R, R¹, R², R³ and R⁴ are defined as in claim
 23. 25. A compoundaccording to claim 24, wherein the compound is(E)-2,4,6-trimethoxystyryl-N-4-methoxyphenyl sulfonamide, or apharmaceutically acceptable salt thereof.
 26. A compound according toclaim 5 wherein at least one of Q₁ and Q₂ is pentasubstituted withhalogen.
 27. A compound according to claim 26 wherein at least one ofQ₁. and Q₂ is pentafluorophenyl.
 28. A compound according to claim 27selected from the group consisting of(E)-4-methoxystyryl-N-2,3,4,5,6-pentafluorophenyl sulfonamide,(E)-styryl -N-2,3,4,5,6-pentafluorophenyl sulfonamide,(E)-4-fluorostyryl-N-2,3,4,5,6-pentafluorophenyl sulfonamide andpharmaceutically acceptable salts thereof.
 29. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier at leastone compound of the formula:

wherein: Q₁ and Q₂ are independently selected from the group consistingof substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl; R is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,(C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl(C₁-C₃)alkyl,substituted heteroaryl(C₁-C₃)alkyl and unsubstitutedheteroaryl(C₁-C₃)alkyl; wherein the substituents for the substitutedaryl and substituted heteroaryl groups comprising Q₁ are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy), trifluoromethyl and

wherein: X is oxygen or sulfur, R⁵ is selected from the group consistingof hydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted phenyl, andunsubstituted phenyl, and R⁶ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl-(C₁-C₃)alkyl and(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl; wherein the substituents for thesubstituted aryl and substituted heteroaryl groups comprising Q₂, andthe substituents for the substituted aryl and substituted heteroarylgroups comprising or included within R, R⁵ and R⁶, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆ alkoxy) and trifluoromethyl;provided, when R is hydrogen and Q₂ is unsubstituted phenyl, then Q₁must be other than dihalophenyl; or a pharmaceutically acceptable saltthereof.
 30. A composition according to claim 29 wherein R is hydrogenor (C₁-C₆)alkyl.
 31. A composition according to claim 30 wherein Q₁ andQ₂ are optionally substituted phenyl.
 32. A composition according toclaim 31 wherein at least one of Q₁ and Q₂ is substituted in at leastthe 4-position.
 33. A composition according to claim 31 wherein thesubstituents are independently selected from the group consisting ofhalogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy nitro, hydroxy and sulfamyl.
 34. Acomposition according to claim 33 wherein the compound is(E)-styryl-N-4-sulfamylphenyl sulfonamide, or a pharmaceuticallyacceptable salt thereof.
 35. A composition according to claim 33 whereinthe compound is (E)-styryl-N-4-chlorophenyl sulfonamide orE)-styryl-N-4-fluorophenyl sulfonamide, or a pharmaceutically acceptablesalt thereof.
 36. A composition according to claim 33 wherein thecompound is (E)-4-methoxystyryl-N-methyl-N-phenyl sulfonamide, or apharmaceutically acceptable salt thereof.
 37. A composition according toclaim 33 wherein the compound is (E)-4-chlorostyryl-N-3-chlorophenylsulfonamide, or a pharmaceutically acceptable salt thereof.
 38. Acomposition according to claim 33 wherein the compound is(E)-4-chlorostyryl-N-2-chlorophenyl sulfonamide, or a pharmaceuticallyacceptable salt thereof.
 39. A composition according to claim 32 whereinQ₁ and Q₂ are both independently substituted in at least the 4-position.40. A composition according to claim 39 wherein the substituents areindependently selected from the group consisting of halogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy nitro, hydroxy and sulfamyl.
 41. Acomposition according to claim 40 wherein the compound is(E)-4-methoxystyryl-N-4-sulfamylphenyl sulfonamide, or apharmaceutically acceptable salt thereof.
 42. A composition according toclaim 40 wherein the compound is(E)-4-chlorostyryl-N-3-fluoro-4-methoxyphenyl sulfonamide, or apharmaceutically acceptable salt thereof.
 43. A composition according toclaim 40 wherein the compound is (E)-4-chlorostyryl-N-4-fluorophenylsulfonamide, or a pharmaceutically acceptable salt thereof.
 44. Acomposition according to claim 40 wherein the compound is(E)-4-methoxystyryl-N-4-fluorophenyl sulfonamide, or a pharmaceuticallyacceptable salt thereof.
 45. A composition according to claim 40 whereinthe compound is (E)-4-methoxystyryl-N-3-fluoro-4-methoxyphenylsulfonamide, or a pharmaceutically acceptable salt thereof.
 46. Acomposition according to claim 40 wherein the compound is(E)-4-methoxystyryl-N-4-fluorophenyl sulfonamide, or a pharmaceuticallyacceptable salt thereof.
 47. A composition according to claim 40 whereinthe compound is (E)-4-fluorostyryl-N-4-chlorophenyl sulfonamide, or apharmaceutically acceptable salt thereof.
 48. A composition according toclaim 40 wherein the compound is(E)-4-methoxystyryl-N-2,4,6-trimethoxyphenyl sulfonamide, or apharmaceutically acceptable salt thereof.
 49. A composition according toclaim 40 wherein the at least one compound is a compound of the formula:

wherein R is hydrogen or (C₁-C₆)alkyl, R¹ is selected from the groupconsisting of halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano,carboxy, carboxy(C₁-C₃)alkoxy, hydroxy, (C₂-C₆)hydroxyalkyl,phosphonato, amino, (C₁-C₆)acylamino, sulfamyl, acetoxy,di(C₁-C₆)alkylamino(C₂-C₆)alkoxy, trifluoromethyl, and R², R³ and R⁴,are independently selected from the group consisting of (C₁-C₆)alkoxy.50. A composition according to claim 49 wherein the at least onecompound is a compound of the formula:

wherein R, R¹, R², R³ and R⁴ are defined as in claim
 49. 51. Acomposition according to claim 50 wherein the compound is(E)-2,4,6-trimethoxystyryl-N-4-methoxyphenyl sulfonamide, or apharmaceutically acceptable salt thereof.
 52. A composition according toclaim 32 wherein at least one of Q₁ and Q₂ is pentasubstituted withhalogen.
 53. A composition according to claim 52 wherein at least one ofQ₁ and Q₂ is pentafluorophenyl.
 54. A method of treating an individualfor a proliferative disorder comprising administering to said individualan effective amount of at least one compound of the formula:

wherein: Q₁ and Q₂ are independently selected from the group consistingof substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl; R is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,(C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl(C₁-C₃)alkyl,substituted heteroaryl(C₁-C₃)alkyl and unsubstitutedheteroaryl(C₁-C₃)alkyl; wherein the substituents for the substitutedaryl and substituted heteroaryl groups comprising Q₁ are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy, trifluoromethyl and

wherein: X is oxygen or sulfur, R⁵ is selected from the group consistingof hydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted phenyl andunsubstituted phenyl, and R⁶ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl-(C₁-C₃)alkyl and(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl; wherein the substituents for thesubstituted aryl and substituted heteroaryl groups comprising Q_(2,) andthe substituents for the substituted aryl and substituted heteroarylgroups comprising or included within R, R⁵ and R⁶, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆ alkoxy) and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 55. A method according toclaim 54 wherein the proliferative disorder is selected from the groupconsisting of hemangiomatosis in new born, secondary progressivemultiple sclerosis, chronic progressive myelodegenerative disease,neurofibromatosis, ganglioneuromatosis, keloid formation, Pagets Diseaseof the bone, fibrocystic disease of the breast, Peronies and Duputren'sfibrosis, restenosis and cirrhosis.
 56. A method according to claim 54wherein the proliferative disorder is cancer.
 57. A method of accordingto claim 56 wherein the cancer is selected from the group consisting ofovarian, breast, prostate, lung, renal, colorectal and brain cancers, orthe cancer is a leukemia.
 58. A method of inducing apoptosis of tumorcells in an individual afflicted with cancer comprising administering tosaid individual an effective amount of at least one compound of theformula:

wherein: Q₁ and Q₂ are independently selected from the group consistingof substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl; R is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,(C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl(C₁-C₃)alkyl,substituted heteroaryl(C₁-C₃)alkyl and unsubstitutedheteroaryl(C₁-C₃)alkyl; wherein the substituents for the substitutedaryl and substituted heteroaryl groups comprising Q₁ are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C1-C6)alkylamino(C₂-C₆)alkoxy, trifluoromethyl and

wherein: X is oxygen or sulfur, R⁵ is selected from the group consistingof hydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted phenyl, andunsubstituted phenyl, and R⁶ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl-(C₁-C₃)alkyl and(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl; and wherein the substituents forthe substituted aryl and substituted heteroaryl groups comprising Q₂,and the substituents for the substituted aryl and substituted heteroarylgroups comprising or included within R, R⁵ and R⁶, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆ alkoxy) and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 59. A method according toclaim 58 wherein the tumor cells are selected from the group consistingof ovarian, breast, prostate, lung, colorectal, renal and brain tumors.60. A method of reducing or eliminating the effects of ionizingradiation on normal cells in a subject who has incurred or is at riskfor incurring exposure to ionizing radiation, comprising administeringto the subject an effective amount of at least one radioprotectivecompound according to the following formula to the subject prior to orafter exposure to ionizing radiation:

wherein: Q₁ and Q₂ are independently selected from the group consistingof substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl; R is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,(C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl(C₁-C₃)alkyl,substituted heteroaryl(C₁-C₃)alkyl and unsubstitutedheteroaryl(C₁-C₃)alkyl; wherein the substituents for the substitutedaryl and substituted heteroaryl groups comprising Q₁ are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy, trifluoromethyl and

wherein: X is oxygen or sulfur, R⁵ is selected from the group consistingof hydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted phenyl andunsubstituted phenyl, and R⁶ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C3)alkyl, unsubstituted aryl-(C1-C3)alkyl and(C1-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl; wherein the substituents for thesubstituted aryl and substituted heteroaryl groups comprising Q_(2,) andthe substituents for the substituted aryl and substituted heteroarylgroups comprising or included within R, R⁵ and R⁶, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆ alkoxy) and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 61. The method of claim 60,wherein the radioprotective compound is administered before exposure tothe ionizing radiation.
 62. The method of claim 61 wherein theradioprotective compound is administered at least about 6 hours beforeexposure to the ionizing radiation.
 63. The method of to claim 62wherein the radioprotective compound is administered no more than about24 hours before exposure to the ionizing radiation.
 64. The method ofclaim 63 wherein the radioprotective compound is administered about 18hours and about 6 hours before exposure to the ionizing radiation. 65.The method of claim 60, wherein the radioprotective compound isadministered after exposure to ionizing radiation.
 66. The method ofclaim 65, wherein the radioprotective compound is administered between0-6 hours after exposure to ionizing radiation.
 67. A method of treatinga subject a proliferative disorder, comprising: (a) administering to thesubject an effective amount of at least one radioprotective compound ofthe formula:

wherein: Q₁ and Q₂ are independently selected from the group consistingof substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl; R is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,(C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl(C₁-C₃)alkyl,substituted heteroaryl(C₁-C₃)alkyl and unsubstitutedheteroaryl(C₁-C₃)alkyl; wherein the substituents for the substitutedaryl and substituted heteroaryl groups comprising Q₁ are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy, trifluoromethyl and

wherein: X is oxygen or sulfur, R⁵ is selected from the group consistingof hydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted phenyl andunsubstituted phenyl, and R⁶ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl-(C₁-C₃)alkyl and(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl; wherein the substituents for thesubstituted aryl and substituted heteroaryl groups comprising Q₂, andthe substituents for the substituted aryl and substituted heteroarylgroups comprising or included within R, R⁵ and R⁶, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy and trifluoromethyl; or apharmaceutically acceptable salt thereof; and (b) administering aneffective amount of therapeutic ionizing radiation.
 68. The method ofclaim 67 wherein the proliferative disorder is cancer.
 69. A method fortreating a subject who has incurred or is at risk for incurringremediable radiation damage from exposure to ionizing radiation,comprising administering an effective amount of at least oneradioprotective compound of the following formula prior to or afterincurring remedial radiation damage from exposure to ionizing radiation:

wherein: Q₁ and Q₂ are independently selected from the group consistingof substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl; R is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,(C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl(C₁-C₃)alkyl,substituted heteroaryl(C₁-C₃)alkyl and unsubstitutedheteroaryl(C₁-C₃)alkyl; wherein the substituents for the substitutedaryl and substituted heteroaryl groups comprising Q₁ are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy, trifluoromethyl and

wherein: X is oxygen or sulfur, R⁵ is selected from the group consistingof hydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted phenyl andunsubstituted phenyl, and R⁶ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl-(C₁-C₃)alkyl and(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl; wherein the substituents for thesubstituted aryl and substituted heteroaryl groups comprising Q₂, andthe substituents for the substituted aryl and substituted heteroarylgroups comprising or included within R, R⁵ and R⁶, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆ alkoxy) and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 70. A process for preparing acompound according to claim 1, comprising reacting a compound of theformula Q₂—CH═CH—SO₂Cl with a compound of the formula Q₁—NRH in anonprotic solvent in the presence of a base to form a compound formula:

wherein: Q₁ and Q₂ are independently selected from the group consistingof substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl; R is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,(C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl(C₁-C₃)alkyl,substituted heteroaryl(C₁-C₃)alkyl and unsubstitutedheteroaryl(C₁-C₃)alkyl; wherein the substituents for the substitutedaryl and substituted heteroaryl groups comprising Q₁ are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy, trifluoromethyl and

wherein: X is oxygen or sulfur, R⁵ is selected from the group consistingof hydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted phenyl andunsubstituted phenyl, and R⁶ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl-(C₁-C₃)alkyl, unsubstituted aryl-(C₁-C₃)alkyl and(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl; and wherein the substituents forthe substituted aryl and substituted heteroaryl groups comprising Q_(2,)and the substituents for the substituted aryl and substituted heteroarylgroups comprising or included within R, R⁵ and R⁶, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy and trifluoromethyl; provided,that when R is hydrogen: (a) when Q₁ is unsubstituted phenyl, Q₂ isother than dimethoxyphenyl, 2-methylphenyl, 2-chlorophenyl,4-chlorophenyl, 4-N,N-dimethylaminophenyl, 4-methylphenyl,4-methoxyphenyl, 4-nitrophenyl, 3-methoxy-4-hydroxyphenyl, unsubstitutedphenyl, unsubstituted pyrenyl, unsubstituted benzodioxolyl,unsubstituted 1-naphthyl and unsubstituted 2-thienyl; (b) when Q₁ is2,4-dinitrophenyl, Q₂ is other than 4-methylphenyl, 4-methoxyphenyl,4-nitrophenyl, 4-bromophenyl, 3,4-dichlorophenyl, unsubstituted phenylor unsubstituted 1-naphthyl; in a sub-embodiment, when Q₁ is2,4-dinitrophenyl, Q₂ is other than 4-alkylphenyl, 4-alkoxyphenyl,4-nitrophenyl, 4-halophenyl, 3,4-dihalophenyl, unsubstituted phenyl orunsubstituted 1 -naphthyl; (c) when Q₁ is 3-hydroxyphenyl, Q₂ is otherthan 2-nitrophenyl, or 3-nitrophenyl; (d) when Q₁ is2-methyl-5-hydroxyphenyl, Q₂ is other than 4-nitrophenyl; (e) when Q₁ isunsubstituted 2-pyridyl, Q2 is other than 3-methoxy-4-hydroxyphenyl; and(f) when Q₂ is unsubstituted phenyl, Q₁ is other than 2-hydroxyphenyl,2-aminophenyl, 3,4-dichlorophenyl or unsubstituted 2-pyridyl; or apharmaceutically acceptable salt thereof.
 71. A process according toclaim 70, provided: (a) when Q₁ is unsubstituted phenyl, Q₂ is otherthan dialkoxyphenyl, 2-alkylphenyl, 2-halophenyl, 4-halophenyl,4-N,N-dialkylaminophenyl, 4-alkylphenyl, 4-alkoxyphenyl, 4-nitrophenyl,3-alkoxy-4-hydroxyphenyl, unsubstituted phenyl, unsubstituted pyrenyl,unsubstituted benzodioxolyl, unsubstituted 1-naphthyl and unsubstituted2-thienyl; (b) when Q₁ is 2,4-dinitrophenyl, Q₂ is other than4-alkylphenyl, 4-alkoxyphenyl, 4-nitrophenyl, 4-halophenyl,3,4-dihalophenyl, unsubstituted phenyl or unsubstituted 1 -naphthyl; (c)when Q₁ is 3-hydroxyphenyl, Q₂ is other than nitrophenyl; (d) when Q₁ is2-methyl-5-hydroxyphenyl, Q₂ is other than 4-nitrophenyl; (e) when Q₁ isunsubstituted 2-pyridyl, Q₂ is other than 3-methoxy-4-hydroxyphenyl; and(f) when Q₂ is unsubstituted phenyl, Q₁ is other than 2-hydroxyphenyl,2-aminophenyl, 3,4-dihalophenyl or unsubstituted 2-pyridyl; or apharmaceutically acceptable salt thereof.
 72. A process for preparing acompound according to claim 1, comprising reacting a compound of theformula

with a compound of the formula Q₂-C(O)H in a nonprotic solvent in thepresence of a base to form a compound formula:

wherein: Q₁ and Q₂ are independently selected from the group consistingof substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl; R is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₆)alkenyl, (C₂-C₆)heteroalkyl,(C₃-C₆)heteroalkenyl, (C₂-C₆)hydroxyalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl(C₁-C₃)alkyl, unsubstituted aryl(C₁-C₃)alkyl,substituted heteroaryl(C₁-C₃)alkyl and unsubstitutedheteroaryl(C₁-C₃)alkyl; wherein the substituents for the substitutedaryl and substituted heteroaryl groups comprising Q₁ are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy, trifluoromethyl and

wherein: X is oxygen or sulfur, R⁵ is selected from the group consistingof hydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted phenyl andunsubstituted phenyl, and R⁶ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₂-C₆)heteroalkyl, substituted aryl,unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl,substituted aryl-(C₁-C₃)alkyl, unsubstituted aryl-(C₁-C₃)alkyl and(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkylenyl; and wherein the substituents forthe substituted aryl and substituted heteroaryl groups comprising Q_(2,)and the substituents for the substituted aryl and substituted heteroarylgroups comprising or included within R, R⁵ and R⁶, are independentlyselected from the group consisting of halogen, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, nitro, cyano, carboxy, carboxy(C₁-C₃)alkoxy, hydroxy,(C₂-C₆)hydroxyalkyl, phosphonato, amino, (C₁-C₆)acylamino, sulfamyl,acetoxy, di(C₁-C₆)alkylamino(C₂-C₆)alkoxy and trifluoromethyl; provided,that when R is hydrogen: (a) when Q₁ is unsubstituted phenyl, Q₂ isother than dimethoxyphenyl, 2-methylphenyl, 2-chlorophenyl,4-chlorophenyl, 4-N-dimethylphenyl, 4-methylphenyl, 4-methoxyphenyl,4-nitrophenyl, 3-methoxy-4-hydroxyphenyl, unsubstituted phenyl,unsubstituted pyrenyl, unsubstituted benzodioxolyl, unsubstituted1-naphthyl and unsubstituted 2-thienyl; (b) when Q₁ is2,4-dinitrophenyl, Q₂ is other than 4-methylphenyl, 4-methoxyphenyl,4-nitrophenyl, 4-bromophenyl, 3,4-dichlorophenyl, unsubstituted phenylor unsubstituted l-naphthyl; (c) when Q₁ is 3-hydroxyphenyl, Q₂ is otherthan 2-nitrophenyl, or 3-nitrophenyl; in a sub-embodiment, when Q₁ is3-hydroxyphenyl, Q₂ is other than nitrophenyl; (d) when Q₁ is2-methyl-5-hydroxyphenyl, Q₂ is other than 4-nitrophenyl; (e) when Q₁ isunsubstituted 2-pyridyl, Q₂ is other than 3-methoxy-4-hydroxyphenyl; and(f) when Q₂ is unsubstituted phenyl, Q₁ is other than 2-hydroxyphenyl,2-aminophenyl, 3,4-dichlorophenyl or unsubstituted 2-pyridyl; or apharmaceutically acceptable salt thereof.
 73. A process for preparing acompound according to claim 72, provided: (a) when Q₁ is unsubstitutedphenyl, Q₂ is other than dialkoxyphenyl, 2-alkylphenyl, 2-halophenyl,4-halophenyl, 4-N,N-dialkylaminophenyl, 4-alkylphenyl, 4-alkoxyphenyl,4-nitrophenyl, 3-alkoxy-4-hydroxyphenyl, unsubstituted phenyl,unsubstituted pyrenyl, unsubstituted benzodioxolyl, unsubstitutedl-naphthyl and unsubstituted 2-thienyl; (b) when Q₁ is2,4-dinitrophenyl, Q₂ is other than 4-alkylphenyl, 4-alkoxyphenyl,4-nitrophenyl, 4-halophenyl, 3,4-dihalophenyl, unsubstituted phenyl orunsubstituted 1-naphthyl; (c) when Q₁ is 3-hydroxyphenyl, Q₂ is otherthan nitrophenyl; (d) when Q₁ is 2-methyl-5-hydroxyphenyl, Q₂ is otherthan 4-nitrophenyl; (e) when Q₁ is unsubstituted 2-pyridyl, Q₂ is otherthan 3-methoxy-4-hydroxyphenyl; and (f) when Q₂ is unsubstituted phenyl,Q₁ is other than 2-hydroxyphenyl, 2-aminophenyl, 3,4-dihalophenyl orunsubstituted 2-pyridyl; or a pharmaceutically acceptable salt thereof.74. A method of reducing the number of malignant cells in bone marrow ofa subject, comprising: (1) removing a portion of the subject's bonemarrow; (2) administering an effective amount of at least oneradioprotective N-aryl-2-arylethenesulfonamide to the bone marrow; (3)irradiating the bone marrow with an effective amount of ionizingradiation.
 75. The method of claim 74, further comprising reimplantingthe bone marrow into the subject.
 76. The method of claim 74, whereinthe subject receives therapeutic ionizing radiation prior toreimplantation of the bone marrow, and is administered at least oneradioprotective N-aryl-2-arylethenesulfonamide prior to receiving thetherapeutic ionizing radiation.
 77. The method of claim 74 wherein theradioprotective compound is administered at least about 6 hours beforeexposure of the bone marrow to the ionizing radiation.
 78. The method ofto claim 74 wherein the radioprotective compound is administered about20 hours before exposure to the ionizing radiation.
 79. The method ofclaim 74 wherein the radioprotective compound is administered about 24hours before exposure to the ionizing radiation.